2,5-Dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase mmp12

ABSTRACT

The invention provides compounds of formula (I) in which L, X, Y, Z 1 , Z 2 , R 1 , R 2 , R 3  and G 2  have the meanings defined in the specification; processes for their preparation; pharmaceutical compositions containing them; a process for preparing the pharmaceutical compositions; and their use in therapy. The compounds of the invention are inhibitors of metalloproteinase MMP12 and are among other things useful for the treatment of obstructive airways diseases, such as asthma and chronic obstructive pulmonary disease (COPD).

The present invention relates to novel compounds, processes for theirpreparation, pharmaceutical compositions containing them and their usein therapy.

Metalloproteinases are a superfamily of proteinases (enzymes) whosenumbers in recent years have increased dramatically. Based on structuraland functional considerations these enzymes have been classified intofamilies and subfamilies as described in N. M. Hooper (1994) FEBSLetters 354:1-6. Examples of metalloproteinases include the matrixmetalloproteinases (MMPs) such as the collagenases (MMP1, MMP8, MMP13),the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMP10, MMP1 1),matrilysin (MMP7), metalloelastase (MMP12), enamelysin (MMP19), theMT-MMPs (MMP14, MMP15, MMP16, MMP17); the reprolysin or adamalysin orMDC family which includes the secretases and sheddases such as TNFconverting enzymes (ADAM 10 and TACE); the astacin family which includeenzymes such as procollagen processing proteinase (PCP); and othermetalloproteinases such as aggrecanase, the endothelin converting enzymefamily and the angiotensin converting enzyme family.

Metalloproteinases are believed to be important in a plethora ofphysiological disease processes that involve tissue remodelling such asembryonic development, bone formation and uterine remodelling duringmenstruation. This is based on the ability of the metalloproteinases tocleave a broad range of matrix substrates such as collagen, proteoglycanand fibronectin. Metalloproteinases are also believed to be important inthe processing, or secretion, of biological important cell mediators,such as tumour necrosis factor (TNF); and the post translationalproteolysis processing, or shedding, of biologically important membraneproteins, such as the low affinity IgE receptor CD23 (for a morecomplete list see N. M. Hooper et al., (1997) Biochem J. 321:265-279).

Metalloproteinases have been associated with many diseases orconditions. Inhibition of the activity of one or more metalloproteinasesmay well be of benefit in these diseases or conditions, for example:various inflammatory and allergic diseases such as, inflammation of thejoint (especially rheumatoid arthritis, osteoarthritis and gout),inflammation of the gastro-intestinal tract (especially inflammatorybowel disease, ulcerative colitis and gastritis), inflammation of theskin (especially psoriasis, eczema, dermatitis); in tumour metastasis orinvasion; in disease associated with uncontrolled degradation of theextracellular matrix such as osteoarthritis; in bone resorptive disease(such as osteoporosis and Paget's disease); in diseases associated withaberrant angiogenesis; the enhanced collagen remodelling associated withdiabetes, periodontal disease (such as gingivitis), corneal ulceration,ulceration of the skin, post-operative conditions (such as colonicanastomosis) and dermal wound healing; demyelinating diseases of thecentral and peripheral nervous systems (such as multiple sclerosis);Alzheimer's disease; extracellular matrix remodelling observed incardiovascular diseases such as restenosis and atheroscelerosis; asthma;rhinitis; and chronic obstructive pulmonary diseases (COPD).

MMP12, also known as macrophage elastase or metalloelastase, wasinitially cloned in the mouse by Shapiro et al [1992, Journal ofBiological Chemistry 267: 4664] and in man by the same group in 1995.MMP12 is preferentially expressed in activated macrophages, and has beenshown to be secreted from alveolar macrophages from smokers [Shapiro etal, 1993, Journal of Biological Chemistry, 268: 23824] as well as infoam cells in atherosclerotic lesions [Matsumoto et al, 1998, Am JPathol 153: 109]. A mouse model of COPD is based on challenge of micewith cigarette smoke for six months, two cigarettes a day six days aweek. Wildtype mice developed pulmonary emphysema after this treatment.When MMP12 knock-out mice were tested in this model they developed nosignificant emphysema, strongly indicating that MMP12 is a key enzyme inthe COPD pathogenesis. The role of MMPs such as MMP12 in COPD (emphysemaand bronchitis) is discussed in Anderson and Shinagawa, 1999, CurrentOpinion in Anti-inflammatory and Immunomodulatory Investigational Drugs1(1): 29-38. It was recently discovered that smoking increasesmacrophage infiltration and macrophage-derived MMP-12 expression inhuman carotid artery plaques Kangavari [Matetzky S, Fishbein MC et al.,Circulation 102:(18), 36-39 Suppl. S, Oct 31, 2000].

A number of metalloproteinase inhibitors are known (see for example thereviews of MMP inhibitors by Beckett R. P. and Whittaker M., 1998, Exp.Opin. Ther. Patents, 8(3):259-282, and by Whittaker M. et al, 1999,Chemical Reviews 99(9):2735-2776).

Published International Patent Application No. WO 02/096426(Bristol-Myers Squibb Company) describes hydantoin derivatives offormula

in which the substituents R¹,R²,R³,R⁴,R⁵,R⁶,R⁷, and R¹¹ are broadlydefined. The derivatives are said, in general terms, to act asinhibitors of metalloproteinases, in particular TACE, MMPs and/oraggrecanase, although no data demonstrating biological is activity isincluded in the application.

We have now discovered a new class of compounds that are potent andselective MMP12 inhibitors and have desirable activity profiles, inparticular they are highly selective inhibitors for MMP12 relative to,for example, MMP14, MMP19 and TACE.

In accordance with the present invention, there is therefore provided acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof

wherein

X represents an oxygen atom or a group NR⁴ or CH₂;

Y represents NH or N-methyl;

Z¹ and Z² each independently represent an oxygen or sulphur atom,provided that at least one of Z¹ and Z² represents an oxygen atom;

Either R¹ represents hydrogen or a group selected from C₁-C₆ alkyl and asaturated or unsaturated 3- to 10-membered ring system which maycomprise at least one ring heteroatom selected from nitrogen, oxygen andsulphur, each group being optionally substituted with at least onesubstituent selected from halogen, hydroxyl, cyano, carboxyl, —NR⁵R⁶,—CONR⁷R⁸, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylcarbonyl(oxy),—S(O)_(m)C₁-C₆ alkyl where m is 0, 1 or 2, C₁-C₆ alkylsulphonylamino,C₁-C₆ alkoxycarbonyl(amino), benzyloxy and a saturated or unsaturated 5-to 6-membered ring which may comprise at least one ring heteroatomselected from nitrogen, oxygen and sulphur, the ring in turn beingoptionally substituted with at least one substituent selected fromhalogen, hydroxyl, oxo (═O), carboxyl, cyano, C₁-C₆ alkyl, C₁-C₆alkoxycarbonyl and C₁-C₆ hydroxyalkyl,

R²represents hydrogen or C₁-C₆ alkl, and

R³represents hydrogen or C₁-C₆ alkyl, or

R¹ and R² together with the carbon atoms to which they are attached forma saturated 5- to 6-membered ring optionally comprising a ringheteroatom selected from nitrogen, oxygen and sulphur, and R³ is asdefined above, or

R² and R³ together with the carbon atom to which they are attached forma saturated 5- to 6-membered ring optionally comprising a ringheteroatom selected from nitrogen, oxygen and sulphur, and R¹ is asdefined above;

R⁴ represents hydrogen or C₁-C₆ alkyl;

R⁵,R⁶,R⁷and R⁸ each independently represent hydrogen or C₁-C₆ alkyloptionally substituted by at least one substituent selected fromhydroxyl, halogen and C₁-C₆ alkoxy;

L represents —CH₂C(O)— or —C(O)CH₂—, or

L represents a C₂-C₆ alkyl or C₂-C₆ alkynyl group optionally interruptedor terminated by at least one moiety selected from O, NH, S, SO, SO₂ andC(O), or L represents a C₃-C₆ cycloalkyl, methylC₃-C₆ cycloalkyl orC₃-C₆ cycloalkylmethyl group, each of the recited groups beingoptionally substituted with at least one substituent selected fromhydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄haloalkoxy, or

L represents a C₃-C₄ alkylene chailn, the ends of which are attached toadjacent ring carbon atoms in the 5- to 10-membered ring system of G² toform a ring;

G² represents a saturated or unsaturated 5- to 10-membered ring systemwhich may comprise at least one ring heteroatom selected from nitrogen,oxygen and sulphur, the ring system being optionally substituted with atleast one substituent selected from halogen, hydroxyl, cyano, nitro,C₁-C₆ alkyl (optionally substituted by one or more of cyano, halogen,hydroxyl and methoxy), C₂-C₆ alkenyl, C₁-C₆ alkoxy (optionallysubstituted by one or more halogen atoms), —S(O)_(n)C₁-C₆ alkyl where nis 0, 1 or 2, C₁-C₆ alkylcarbonyl(amino), C₁-C₆ alkylcarbonyloxy,phenyl, benzyloxy, —NR⁹R¹⁰ and a group of formula

R⁹ and R¹⁰ each independently represent hydrogen or C₁-C₆ alkyloptionally substituted by at least one substituent selected fromhydroxyl, halogen and C₁-C₆ alkoxy;

M represents a bond or —O—, —S—, —C≡C—, —CH₂O— or —OCH₂—;

G³ represents an unsaturated 5- to 10-membered ring system which maycomprise at least one ring heteroatom selected from nitrogen, oxygen andsulphur, the ring system being optionally substituted with at least onesubstituent selected from halogen, hydroxyl, cyano, nitro, C₁-C₆ alkyl(optionally substituted by one or more of cyano, halogen, hydroxyl andmethoxy), C₂-C₆ alkenyl, C₁-C₆ alkoxy (optionally substituted by one ormore halogen atoms), —S(O)_(t)C₁-C₆ alkyl where t is 0, 1 or 2, C₁-C₆alkylcarbonyl(amino), C₁-C₆ alkylcarbonyloxy, phenyl, benzyloxy and—NR¹¹R¹² ; and

R¹¹ and R¹² each independently represent hydrogen or C₁-C₆ alkyloptionally to substituted by at least one substituent selected fromhydroxyl, halogen and C₁-C₆ alkoxy.

In the context of the present specification, unless otherwise stated, analkyl, alkenyl or alkynyl substituent group or an alkyl moiety in asubstituent group may be linear or branched. A haloalkyl or haloalkoxysubstituent group will comprise at least one halogen atom, e.g. one,two, three or four halogen atoms. A hydroxyalkyl substituent may containone or more hydroxyl groups but preferably contains one or two hydroxylgroups. When R¹ and R²,or R² and R³,form a ring, it should be understoodthat the ring may comprise up to one ring heteroatom only. In thedefinition of R¹, it should be noted that each of the saturated orunsaturated 3- to 10-membered ring system and the saturated orunsaturated 5- to 6-membered ring may have alicyclic or aromaticproperties. The same comment applies to the saturated or unsaturated 5-to 10-membered ring system in the definition of G². An unsaturated ringsystem will be partially or fully unsaturated. When L represents a C₂-C₆alkyl or C₂-C₆ alkynyl group optionally interrupted or terminated bymore than one moiety (e.g. two moieties) selected from O, NH, S, SO, SO₂and C(O), it may in some instances be possible for the two moieties tobe adjacent to one another but otherwise the moieties will need to beseparated by one or more carbon atoms. For example, whilst it isacceptable for C(O) or SO₂ and NH to be adjacent to one another,combinations such as NH—NH, NH—O, O—SO, O—SO₂, SO—SO, SO₂—SO₂ and so onare undesirable. The person skilled in the art will know which moietiesmay be placed next to one another.

In an embodiment of the invention, X represents an oxygen atom or agroup NR⁴ where R⁴ represents hydrogen or C₁-C₆, preferably C₁-C₄, alkyl(e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl).

In another embodiment of the invention, X represents NH or N-methyl. Ina further embodiment, X represents NH.

In one embodiment, Z¹ and Z² both represent an oxygen atom.

In an embodiment of the invention, R¹ represents hydrogen or a groupselected from C₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl)and a saturated or unsaturated 3- to 10-membered ring system which maycomprise at least one ring heteroatom (e.g. one, two, three or four ringheteroatoms independently) selected from nitrogen, oxygen and sulphur,each group being optionally substituted with at least one substituent(e.g. one, two, three or four substituents independently) selected fromhalogen (e.g. chlorine, fluorine, bromine or iodine), hydroxyl, cyano,carboxyl, —NR⁵R⁶, —CONR⁷R⁸, C₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl orn-hexyl), C₁-C₆, preferably C₁-C₄, alkoxy (e.g. methoxy, ethoxy,n-propoxy or n-butoxy), C₁-C₆, preferably C₁-C₄, alkylcarbonyl(oxy)(e.g. methylcarbonyl(oxy), ethylcarbonyl(oxy), n-propylcarbonyl(oxy),isopropylcarbonyl(oxy), n-butylcarbonyl(oxy), n-pentylcarbonyl(oxy) orn-hexylcarbonyl(oxy)), —S(O)_(m)C₁-C₆, preferably C₁-C₄, alkyl where mis 0, 1 or 2 (e.g. methylthio, ethylthio, methylsulphinyl,ethylsulphinyl, methylsulphonyl or ethylsulphonyl), C₁-C₆, preferablyC₁-C₄, alkylsulphonylamino (e.g. methylsulphonylamino,ethylsulphonylaamino, n-propylsulphonylamino, isopropylsulphonylamino,n-butylsulphonylamino, n-pentylsulphonylamino or n-hexylsulphonylamino),C₁-C₆, preferably C₁-C₄, alkoxycarbonyl(amino) (e.g.methoxycarbonyl(amino), ethoxycarbonyl(amino), n-propoxycarbonyl(amino)or n-butoxycarbonyl(amino)), benzyloxy and a saturated or unsaturated 5-to 6-membered. ring which may comprise at least one ring heteroatom(e.g. one, two, three or four ring heteroatoms independently) selectedfrom nitrogen, oxygen and sulphur, the ring in turn being optionallysubstituted with at least one substituent (e.g. one, two or threesubstituents independently) selected from halogen (e.g. chlorine,fluorine, bromine or iodine), hydroxyl, oxo, carboxyl, cyano, C₁-C₆,preferably C₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), C₁-C₆, preferablyC₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl) andC₁-C₆, preferably C₁-C₄, hydroxyalkyl (e.g. —CH₂OH, —CH₂CH₂OH,—CH₂CH₂CH₂OH or —CH(OH)CH₃); R² represents hydrogen or C₁-C₆, preferablyC₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl or n-hexyl); and R³ represents hydrogenor C₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).

Examples of saturated or unsaturated 3- to 10-membered ring systems thatmay be used, which may be monocyclic or polycyclic (e.g. bicyclic) inwhich the two or more rings are fused, include one or more (in anycombination) of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptyl, cyclopentenyl, cyclohexenyl, phenyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,diazabicyclo[2.2.1]hept-2-yl, naphthyl, benzofuranyl, benzothienyl,benzodioxolyl, quinolinyl, 2,3-dihydrobenzofuranyl, tetrahydropyranyl,pyrazolyl, pyrazinyl, thiazolidinyl, indanyl, thienyl, isoxazolyl,pyridazinyl, thiadiazolyl, pyrrolyl, firanyl, thiazolyl, indolyl,imidazolyl, pyrimidinyl, benzimidazolyl, triazolyl, tetrazolyl andpyridinyl. Preferred ring systems include phenyl, pyridinyl andtetrahydropyranyl.

Examples of saturated or unsaturated 5- to 6-membered ring substituentsin R¹ include cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiomorpholinyl, pyrazolyl, pyrazinyi, pyridazinyl, thiazolidinyl,thienyl, isoxazolyl, pyrimidinyl, thiadiazolyl, pyrrolyl, furanyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl and pyridinyl. Preferredrings include morpholinyl, pyrimidinyl, phenyl, irnidazolyl,piperidinyl, tetrahydropyranyl and triazolyl.

Particular values for R¹ include the following:

In another embodiment of the invention, R¹ represents hydrogen or agroup selected from C₁-C₄ alkyl and a saturated or unsaturated 5- to10-membered ring system which may comprise at least one ring heteroatom(e.g. one, two, three or four ring heteroatoms independently) selectedfrom nitrogen, oxygen and sulphur, each group being optionallysubstituted with at least one substituent (e.g. one, two, three or foursubstituents independently) selected from halogen, hydroxyl, cyano,carboxyl, —NR⁵R⁶, —CONR⁷R⁸, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylcarbonyl(oxy), —S(O)_(m)C₁-C₄ alkyl where m is 0, 1 or 2, C₁-C₄alkylsulphonylamino, C₁-C₄ alkoxycarbonyl(amino), benzyloxy and asaturated or unsaturated 5- to 6-membered ring which may comprise atleast one ring heteroatom (e.g. one, two, three or four ring heteroatomsindependently) selected from nitrogen, oxygen and sulphur, the ring inturn being optionally substituted with at least one substituent (e.g.one, two or three substituents independently) selected from halogen,hydroxyl, oxo, carboxyl, cyano, C₁-C₄ alkyl C₁-C₄ alkoxycarbonyl andC₁-C₄ hydroxyalkyl;

R² represents hydrogen or C₁-C₄ alkyl; and

R³ represents hydrogen or C₁-C₄ alkyl.

In still another embodiment, R¹ represents hydrogen or C₁-C₄ alkyl,particularly methyl; R² represents hydrogen; and R³ represents hydrogen.

Alternatively, R¹ and R² may together with the carbon atoms to whichthey are attached form a saturated 5- to 6-membered ring optionallycomprising a ring heteroatom selected from nitrogen, oxygen and sulphur(e.g. cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl,tetrahydrofuranyl or tetrahydrothiophenyl), and R³ is as previouslydefined.

As a further alternative, R² and R³ may together with the carbon atom towhich they are attached form a saturated 5- to 6-membered ringoptionally comprising a ring heteroatom selected from nitrogen, oxygenand sulphur (e.g. cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl,tetrahydrofuranyl or tetrahydrothiophenyl), and R¹ is as previouslydefined. R⁵, R⁶, R⁷ and R⁸ each independently represent hydrogen orC₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionallysubstituted by at least one substituent (e.g. one, two or threesubstituents independently) selected from hydroxyl, halogen (e.g.chlorine, fluorine, bromine or iodine) and C₁-C₆, preferably C₁-C₄,alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy).

In an embodiment of the invention, R⁵, R⁶, R⁷ and R⁸ each independentlyrepresent hydrogen or C₁-C₆, preferably C₁-C₄, alkyl. In anotherembodiment, R⁵, R⁶, R⁷ and R⁸ each independently represent hydrogen.

L represents —CH₂C(O)— or —C(O)CH₂—, or

L represents a C₂-C₆, preferably C₂-C₄, alkyl or C₂-C₆, preferablyC₂-C₄, alkynyl group optionally interrupted or terminated by at leastone moiety (e.g. one or two moieties independently) selected from O ,NH, S, SO, SO₂ and C(O) (for example, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, —(CH₂)₆—, —C≡C—, -CH₂—C≡C—, —C≡CH₂—, —O—(CH₂)₃—NH—,—NH—(CH₂)₃—O—, —CH(CH₃)—, —(CH₂)₂—C(O)—, —C(O)—(CH₂)₂—, —CH₂CH(CH₃)—,—CH(CH₃)CH₂—, —(CH₂)₂—O—CH₂— or —CH₂—O—(CH₂)₂), or L represents a C₃-C₆cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl),methylC₃-C6 cycloalkyl (e.g. methylcyclopropyl) or C₃-C₆cycloalkylmethyl (e.g. cyclopropylmethyl) group, each of the recitedgroups being optionally substituted with at least one substituent (e.g.one, two or three substituents independently) selected from hydroxyl,halogen (e.g. chlorine, fluorine, bromine or iodine), C₁-C₄, preferablyC₁-C₂, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl ort-butyl), C₁-C₄, preferably C₁-C₂, haloalkyl (e.g. trifluoromethyl orpentafluoroethyl), C₁-C₄, preferably C₁-C₄, alkoxy (e.g. methoxy orethoxy) and C₁-C₄, preferably C₁-C₂, haloalkoxy (e.g. trifluoromethoxy)(such as —CH₂OCH(R)CH₂NH— or —NHCH₂CH(R)OCH₂—where R represents methyl,hydroxyl or methoxy, —CH(CH₃)—CH(OH)—, —CH(OH)—CH(CH₃)—, —CH₂CH(OH)—,—CH(OH)CH₂—, —CH₂CH(OCH₃)— or —CH(OCH₃)CH₂—), or

L represents a C₃-C₄ alkylene chain, the ends of which are attached toadjacent ring carbon atoms in the 5- to 10-membered ring system of G² toform a ring (for example, if G² represents an unsubstituted phenyl groupand L represents a C₃ alkylene chain, G² and L together form a2,3-dihydroinden-2-yl group having the structure:

In an embodiment of the invention, reading from left to right in formula(I),

L represents —C(O)CH₂—, or

L represents C₂-C₄ alkyl optionally interrupted or terminated by anoxygen atom, cyclopropyl or cyclopropylmethyl, each of which isoptionally substituted with one or two substituents independentlyselected from hydroxyl, halogen, methyl, trifluoromethyl, methoxy andtrifluoromethoxy, or

L represents a C₃-C₄ alkylene chain, the ends of which are attached toadjacent ring carbon atoms in the 5- to 10-membered ring system of G² toform a ring.

In a further embodiment of the invention, L represents (reading fromleft to right in formula (I)) —C(O)CH₂—, —(CH₂)₂—, —CH(CH₃)—,—CH(CH₃)CH₂—, —CH(OH)—CH(CH₃)—, —CH(OH)CH₂—, —CH(OCH₃)CH₂—,—CH₂—O—(CH₂)₂, cyclopropyl, cyclopropylmethyl, or

L represents a C₃ alkylene chain, the ends of which are attached toadjacent ring carbon atoms in the 5- to 10-membered ring system of G² toform a ring.

G² represents a saturated or unsaturated 5- to 10-membered ring systemwhich may comprise at least one ring heteroatom (e.g. one, two, three orfour ring heteroatoms independently) selected from nitrogen, oxygen andsulphur, the ring system being optionally substituted with at least onesubstituent (e.g. one, two, three or four substituents independently)selected from halogen (e.g. chlorine, fluorine, bromine or iodine),hydroxyl, cyano, nitro, C₁-C₆, preferably C₁-C₄, alkyl such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl orn-hexyl (optionally substituted by one or more, e.g. one, two or three,substituents independently selected from cyano, halogen such aschlorine, fluorine, bromine or iodine, hydroxyl and methoxy), C₂-C₆,preferably C₂-C₄, alkenyl (e.g. ethenyl, prop-1-enyl, prop-2-enyl,but-1-enyl, pent-1-enyl, hex-1-enyl or 2-methyl-pent-2-enyl), C₁-C₆,preferably C₁-C₄, alkoxy such as methoxy, ethoxy, n-propoxy or n-butoxy(optionally substituted by one or more, e.g. one, two or three, halogenatoms such as chlorine, fluorine, bromine or iodine), —S(O)_(n)C₁-C₆,preferably C₁-C₄, alkyl where n is 0, 1 or 2 (e.g. methylthio,ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl orethylsulphonyl), C₁-C₆, preferably C₁-C₄, alkylcarbonyl(amino) (e.g.methylcarbonyl(amino), ethylcarbonyl(amino), n-propylcarbonyl(amino),isopropylcarbonyl(amino), n-butylcarbonyl(amino),n-pentylcarbonyl(amino) or n-hexylcarbonyl(amino)), C₁-C₆, preferablyC₁-C₄, alkylcarbonyloxy (e.g. methylcarbonyloxy, ethylcarbonyloxy,n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy,n-pentylcarbonyloxy or n-hexylcarbonyloxy), phenyl, benzyloxy, —NR⁹R¹⁰and a group of formula

Examples of saturated or unsaturated 5- 10-membered ring systems thatmay be used in G²,which may be monocyclic or polycyclic (e.g. bicyclic)in which the two or more rings are fused, include one or more (in anycombination) of cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl,cyclopentenyl, cyclohexenyl, phenyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, diazabicyclo[2.2.1]hept-2-yl,naphthyl, benzofuranyl, benzothienyl, benzodioxolyl, quinolinyl,2,3-dihydrobenzofuranyl, tetrahydropyranyl, pyrazolyl, pyrazinyl,thiazolidinyl, indanyl, thienyl, isoxazolyt, pyridazinyl, thiadiazolyl,pyrrolyl, furanyl, thiazolyl, indolyl, imidazolyl, pyrirnidinyl,benzimidazolyl, triazolyl, tetrazolyl and pyridinyl. Preferred ringsystems include phenyl, indolyl, thienyl and piperidinyl.

R⁹ and R¹⁰ each independently represent hydrogen or C₁-C₆, preferablyC₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by atleast one substituent (e.g. one, two or three substituentsindependently) selected from hydroxyl, halogen (e.g. chlorine, fluorine,bromine or iodine) and C₁-C₆, preferably C₁-C₄, alkoxy (e.g. methoxy,ethoxy, n-propoxy or n-butoxy).

In an embodiment of the invention, G² represents a saturated orunsaturated 5- to 9-membered ring system which may comprise one ringheteroatom selected from nitrogen, oxygen and sulphur, the ring systembeing optionally substituted with one or two substituents independentlyselected from halogen, hydroxyl, cyano, nitro, C₁-C₄ alkyl (optionallysubstituted by one or more, e.g. one, two or three, substituentsindependently selected from cyano, halogen such as chlorine, fluorine,bromine or iodine, hydroxyl and methoxy), C₂-C₄ alkenyl, C₁-C₄ alkoxy(optionally substituted by one or more, e.g. one, two or three, halogenatoms such as chlorine, fluorine, bromine or iodine), —S(O)_(n)C₁-C₄alkyl where n is 0, 1 or 2, C₁-C₄ alkylcarbonyl(amino), C₁-C₄alkylcarbonyloxy, phenyl, benzyloxy, —NR⁹R¹⁰ and a group of formula

In another embodiment, G² represents a saturated or unsaturated 5- to9-membered ring system which may comprise one ring heteroatom selectedfrom nitrogen and sulphur (e.g. phenyl, indolyl, thienyl orpiperidinyl), the ring system being optionally substituted with one ortwo substituents independently selected from halogen, C₁-C₄ alkyl and agroup of formula

In an embodiment of the invention, M represents a bond, —O—or —C≡C—. Ina further embodiment, M represents a bond.

G³ represents an unsaturated 5- to 10-membered ring system which maycomprise at least one ring heteroatom (e.g. one, two, three or four ringheteroatoms independently) selected from nitrogen, oxygen and sulphur,the ring system being optionally substituted with at least onesubstituent (e.g. one, two, three or four substituents independently)selected from halogen (e.g. chlorine, fluorine, bromine or iodine),hydroxyl, cyano, nitro, C₁-C₆, preferably C₁-C₄, alkyl such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl orn-hexyl (optionally substituted by one or more, e.g. one, two or three,substituents independently selected from cyano, halogen such aschlorine, fluorine, bromine or iodine, hydroxyl and methoxy), C₂-C₆,preferably C₂-C₄, alkenyl (e.g. ethenyl, prop-1-enyl, prop-2-enyl,but-1-enyl, pent-1-enyl, hex-1-enyl or 2-methyl-pent-2-enyl), C₁-C₆,preferably C₁-C₄, alkoxy such as methoxy, ethoxy, n-propoxy or n-butoxy(optionally substituted by one or more, e.g. one, two or three, halogenatoms such as chlorine, fluorine, bromine or iodine), —S(O)_(t)C₁-C₆,preferably C₁-C₄, alkyl where t is 0, 1 or 2 (e.g. methylthio,ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl orethylsulphonyl), C₁-C₆, preferably C₁-C₁-C₄, alkylcarbonyl(amino) (e.g.methylcarbonyl(amino), ethylcarbonyl(amino), n-propylcarbonyl(amino),isopropylcarbonyl(amino), n-butylcarbonyl(amino),n-pentylcarbonyl(amino) or n-hexylcarbonyl(amino)), C₁-C₆, preferablyC₁-C₄, alkylcarbonyloxy (e.g. methylcarbonyloxy, ethylcarbonyloxy,n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy,n-pentylcarbonyloxy or n-hexylcarbonyloxy), phenyl, benzyloxy and—NR¹¹R¹².

Examples of unsaturated 5- to 10-membered ring systems that may be usedin G³, which may be monocyclic or polycyclic (e.g. bicyclic) in whichthe two or more rings are fused, include one or more (in anycombination) of cyclopentenyl, cyclohexenyl, phenyl, naphthyl,benzofuranyl, benzothienyl, benzodioxolyl, quinolinyl,2,3-dihydrobenzofuranyl, pyrazolyl, pyrazinyl, thiazolidinyl, indanyl,thienyl, isoxazolyl, pyridazinyl, thiadiazolyl, pyrrolyl, furanyl,thiazolyl, indolyl, imnidazolyl, pyrimidinyl, benzimidazolyl, triazolyl,tetrazolyl and pyridinyl. Preferred ring systems include phenyl,thienyl, naphthyl, benzofuranyl, benzothienyl, pyridinyl, pyrrolyl,furanyl, benzodioxolyl, quinolinyl and 2,3-dihydrobenzofuranyl.

R¹¹ and R¹² each independently represent hydrogen or C₁-C₆, preferablyC₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by atleast one substituent (e.g. one, two or three substituentsindependently) selected from hydroxyl, halogen (e.g. chlorine, fluorine,broniine or iodine) and C₁-C₆, preferably C₁-C₄, alkoxy (e.g. methoxy,ethoxy, n-propoxy or n-butoxy).

In one embodiment, G³ represents an unsaturated 5- to 10-membered ringsystem which may comprise one or two ring heteroatoms independentlyselected from nitrogen, oxygen and sulphur (e.g. phenyl, thienyl,naphthyl, benzofuranyl, benzothienyl, pyridinyl, pyrrolyl, furanyl,benzodioxolyl, quinolinyl and 2,3-dihydrobenzofuranyl), the ring systembeing optionally substituted with one or two substituents independentlyselected from halogen, hydroxyl, cyano, nitro, C₁-C₄ alkyl (optionallysubstituted by one or more, e.g. one, two or three, substituentsindependently selected from cyano, halogen such as chlorine, fluorine,bromine or iodine, hydroxyl and methoxy), C₂-C₄ alkenyl, C₁-C₄ alkoxy(optionally substituted by one or more, e.g. one, two or three, halogenatoms such as chlorine, fluorine, bromine or iodine), —S(O)_(t)C₁-C₄alkyl where t is 0, 1 or 2, C₁-C₄ alkylcarbonyl(amino), C₁-C₄alkylcarbonyloxy, phenyl, benzyloxy and —NR¹¹R¹²

In another embodiment, G³ represents an unsaturated 5- to 10-memberedring system which may comprise one or two ring heteroatoms independentlyselected from nitrogen, oxygen and sulphur (e.g. phenyl, thienyl,naphthyl, benzofuranyl, benzothienyl, pyridinyl, pyrrolyl, furanyl,benzodioxolyl, quinolinyl and 2,3-dihydrobenzofuranyl), the ring systembeing optionally substituted with one or two substituents independentlyselected from halogen, cyano, nitro, C₁-C₄ alkyl (optionally substitutedby one or more, e.g. one, two or three, substituents independentlyselected from cyano and halogen), C₁-C₄ alkoxy (optionally substitutedby one or more, e.g. one, two or three, halogen atoms), C₁-C₄ alkylthio,C₁-C₄ alkylcarbonyl(amino), phenyl and benzyloxy.

In still another embodiment, G³ represents an unsaturated 5- to10-membered ring system which may comprise one or two ring heteroatomsindependently selected from nitrogen, oxygen and sulphur (e.g. phenyl,thienyl, naphthyl, benzofuranyl, beniothienyl, pyridinyl, is pyrrolyl,furanyl, benzodioxolyl, quinolinyl and 2,3-dihydrobenzofuranyl), thering system being optionally substituted with one or two substituentsindependently selected from fluorine, chlorine, cyano, nitro, methyl,cyanomethyl, trifluoromethyl, methoxy, trifluoromethoxy, methylthio,methylcarbonyl (acetyl), methylcarbonylamino (acetylamino), phenyl andbenzyloxy.

Particular values for G² include the following:

In an embodiment of the invention:

X represents —NH— or —N(CH₃)—;

Y represents NH;

Z¹ and Z² both represent an oxygen atom;

R¹ represents hydrogen or methyl;

R² represents hydrogen;

R³ represents hydrogen;

L represents —C(O)CH₂—, —(CH₂)₂—, —CH(CH₃)—, —CH(CH₃)CH₂—,—CH(OH)—CH(CH₃)—, —CH(OH)CH₂—, —CH(OCH₃)CH₂—, —CH₂—O—(CH₂)₂,cyclopropyl, cyclopropylmethyl, or

L represents a C₃ alkylene chain, the ends of which are attached toadjacent ring carbon atoms in the 5- to 9-membered ring system of G² toform a ring;

G² represents represents a saturated or unsaturated 5- to 9-memberedring system which may comprise one ring heteroatom selected fromnitrogen and sulphur, the ring system being optionally substituted withone or two substituents independently selected from halogen, C₁-C₄ alkyland a group of formula

M represents a bond, —O— or —C≡C—; and

G³ represents an unsaturated 5- to 10-membered ring system which maycomprise one or two ring heteroatoms independently selected fromnitrogen, oxygen and sulphur, the ring system being optionallysubstituted with one or two substituents independently selected fromfluorine, chlorine, cyano, nitro, methyl, cyanomethyl, trifluoromethyl,methoxy, trifluoromethoxy, methylthio, methylcarbonyl,methylcarbonylamino, phenyl and benzyloxy.

Examples of compounds of the invention include:

-   2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-fluoro-biphenyl-4-yl)-ethyl]-acetamide,-   N-[2-(4′-Cyano-biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-(2-phenyl-cyclopropyl)-acetamide,-   N-[2-(4-Chlorophenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-(2-Biphenyl-4-yl-ethyl)-2-(2,5-dioxoiridazolidin-4-yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(7-methyl-1H-indol-3-yl)ethyl]-acetamide,-   2-(2,S-Dioxoimidazolidin-4-yl)-N-[2-(4-phenoxyphenyl)ethyl]-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-fluorophenyl)ethyl]-acetamide,-   N-[2-(4-Bromophenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(2,4-Dichlorophenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(3′-Chloro-biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(4′-Benzyloxy-biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-thiophen-3-yl-phenyl)ethyl]-acetamide,-   2-(2,5-Dioxoimidazolidin-4yl)-N-[2-(4-thiophen-2-yl-phenyl)ethyl]-acetamide,-   N-[2-(4′-Chloro-biphenylyl)-ethyl]-2-(2,5-dioxoinidazolidin-4-yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4yl)-N-[2-(4′-methylsulfanyl-biphenyl-4-yl)ethyl]-acetamide,-   2-(2,5-Dioxoimidazolidin-4yl)-N-[2-(3′-nitro-biphenyl-4-yl)ethyl]-acetamide,-   2-(2,5-Dioxoimidazolidin-4yl)-N-[2-(4′-methyl-biphenyl-4-yl)ethyl]-acetarnide,-   N-[2-(3′-Acetylamino-biphenyl-4-yl)ethyl]-2-(2,5-dioxoidazolidin4yl)-acetamide,-   2-(2,5-Dioxoiridazolidin-4yl)-N-[2-(4-naphthalen-2-yl-phenyl)ethyl]-acetamide,-   N-[2-(3′,5′-Dichloro-biphenyl-4-yl)ethyl]-2-(2,5-dioxoimidazohdin-4-yl)-acetamide,-   2-(2,5-Dioxoinidazolidin-4yl)-N-[2-(3′-methyl-biphenyl-4-yl)ethyl]-acetamide,-   N-[2-(4-Benzofuran-2-yl-phenyl)ethyl]-2-2,5-dioxoimidazolidin-4yl)-acetamide,-   2-(2,5-Dioxoimidazolidinyl)-N-[2-(3′-methoxy-biphenyl-4-yl)ethyl]-acetamide,-   2-(2,5-Dioxoimidazolidinyl)-N-(2-[1,1′;4′,1″]terphenyl-4-ylethyl)-acetamide,-   N-[2-(4′-Acetyl-biphenylyl)ethyl)-2-(2,5dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(4-Benzo[b]thiophen-2-yl-phenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(4′-Cyanomethyl-biphenyl-4-yl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4pyridin-3-yl-phenyl)ethyl]-acetamide,-   2-(2,5-Dioxoimidazolidin-4yl)-N-{2-[4-(1H-pyrrol-2-yl)phenyl]ethyl    }-acetamide,-   2-(2,5-Dioxoimidazolidin-4yl)-N-[2-(4-furan-3-yl-phenyl)ethyl]-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-furan-2-yl-phenyl)ethyl]-acetamide,-   2-(2,5-Dioxoirmidazolidin-4-yl)-N-(2-thiophen-2-yl-ethyl)-acetamide,-   N-[2-(4-tert-Butylphenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(4-Chlorophenyl)-1-methylethyl]-2-(2,5-dioxoimidazolidin-4-yl)acetamide,-   N-{[1-(4-Chlorophenyl)cyclopropyl]methyl}-2-(2,5-dioxoimidazolidin-4-yl)acetamide,-   N-2,3-Dihydro-1H-inden-2-yl-2-(2,5-dioxoimidazolidin-4-yl)acetamide,-   N-[2-(4-Chlorophenyl)ethyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamide,-   N-[2-(4-Chlorophenyl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamide,-   N-[2-(4′-Cyano-1,1    ′-biphenyl-4-yl)ethyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamide,-   N-[2-(4′-Fluoro-1,1    ′-biphenyl-4-yl)ethyl]-2-(methyl-2,5-dioxoimidazolidin-4-    yl)acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-fluoro-1,1′-biphenyl-4yl)propyl]-acetamide,-   N-[(1S,2R)-2-(4′-Methoxybiphenyl-4-yl)cyclopropyl]-2-(4-methyl-2,5-dioxoimidazolidin-4yl)-acetamide,-   N-[(1S,2R)-2-(4′-Cyanobiphenyl-4-yl)cyclopropyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   is    N-[(1S,2R)-2-(4′-Acetylbiphenyl-4-yl)cyclopropyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-{(1S,2R)-2-[4′-(Acetylamino)biphenyl-4-yl]cyclopropyl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(4′-Cyanobiphenyl-4-yl)propyl]-2-(4methyl-2,5-dioxoimidazolidin-4-yl)-20    acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-3′-methoxybiphenyl-4-yl)ethyl]-acetamide,-   N-[2-(4′-Cyano-3′-methylbiphenyl-4-yl)propyl]-2-4-methyl-2,5-dioxoimidazolidin-4-    yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-methyl-N-(2-phenylethyl)-acetamide,-   N-[1-(4-Chlorophenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-(2-hydroxy-1-methyl-2-phenylethyl)-acetamide,-   N-{2-[4(1,3-Benzodioxol-5-yl)phenyl]propyl    }-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(3′-methoxybiphenyl-4-yl)propyl]-acetamide,-   N-{2-[3′-(Acetylamino)biphenyl-4-yl]propyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(3′-Acetylbiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(4′-Acetylbiphenylyl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-{2-[4-(1-Benzothien-2-yl)phenyl]propyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(3′-Cyanobiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(4′-Cyanobiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4yl)-N-[2-(4′-fluoro-3′-methylbiphenyl-4-yl)propyl]-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[3′-(methylthio)biphenyl-4-yl]propyl    }-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-}2-[4-(6-methoxypyridin-3-yl)phenyl]propyl}-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-methoxy-3′-methylbiphenyl-4-yl)propyl]-acetamide,-   N-{2-[4-(2,3-Dihydro-1-benzofuran-5-yl)phenyl]propyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[3′-(trifluoromethoxy)biphenyl-4-yl]propyl}-acetamide,-   N-[2-(3′,4′-Dimethoxybiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4quinolin-3-ylphenyl)propyl]-acetamide,-   N-[2-(4′-Cyano-3′-methylbiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[5-(1,3-Benzodioxol-5-yl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoirmidazolidin-4-yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-[5-(3-methoxyphenyl)-2,3-dihydro-1H-inden-2-yl]-acetamide,-   N-{5-[3-(Acetylarnino)phenyl]-2,3-dihydro-1H-inden-2-yl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[5-(3-Acetylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[5-(4-Acetylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[5-(1-Benzothien-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetanide,-   N-[5-(3-Cyanophenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-(5-(4-Cyanophenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4yl)-N-[5-(4-fluoro-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-{5-[3-(methylthio)phenyl]-2,3-dihydro-1H-inden-2-yl    }-acetamide,-   2-(2,5-Dioxoimidazolidin-4yl)-N-[5-(6-methoxypyridin-3-yl)-2,3-dihydro-1H-inden-2-yl]-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-[5-(4-methoxy-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-acetamide,-   N-[5-(2,3-Dihydro-1-benzofuran-5-yl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)acetamide,-   N-[5-(3    ,4-Dimethoxyphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(4′-Fluorobiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-{2-[4-(1,3-Benzodioxol-5-yl)phenyl]propyl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(3′-Methoxybiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-{2-[4-(1-Benzothien-2-yl)phenyl]propyl    }-2-(4-methyl-2,5-dioxoimidazolidin4-yl)-acetamide,-   N-[2-(3′-Cyanobiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(4′-Fluoro-3′-methylbiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-{2-[3′-(methylthio)biphenyl-4-yl]propyl    }-acetamide,-   N-{2-[4-(6-Methoxypyridin-3-yl)phenyl]propyl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(4′-Methoxy-3    ′-methylbiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-{2-[4-(2,3-Dihydro-1-benzofuran-5-yl)phenyl]propyl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-{2-[3′-(trifluoromethoxy)biphenyl-4yl]propyl    }-acetamide,-   N-[2-(3′,4′-Dimethoxybiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-[2-(4-quinolin-3-ylphenyl)propyl]-acetamide,-   N-[5-(4-Fluorophenyl)-2,3dihydro-1H-inden-2-yl]-2-(4methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[5-(1    ,3-Benzodioxol-5-yl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[5-(3-Methoxyphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-{5-[3-(Acetylamino)phenyl]-2,3-dihydro-1H-inden-2-yl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[5-(3-Acetylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[5-(4-Acetylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[5-(1-Benzothien-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[5-(3-Cyanophenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[5-(4-Cyanophenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4yl)-acetamide,-   N-[5-(4-Fluoro-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4yl)-acetamide,-   2-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-(5-[3-(methylthio)phenyl]-2,3-dihydro-1H-inden-2-yl}-acetamide,-   N-[5-(6-Methoxypyridin-3-yl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[5-(4-Methoxy-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[5-(2,3-Dihydro-1-benzofuran-5-yl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-{5-[3-(trifluoromethoxy)phenyl]-2,3-dihydro-1H-inden-2-yl}-acetamide,-   N-[5-(3,4-Dimethoxyphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[5-(4-Cyano-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-(2-{4-[4-(trifluoromethyl)phenoxy]phenyl    }ethyl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[4-(4-methoxyphenoxy)phenyl]ethyl}-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-(2-{4-[4-(trifluoromethoxy)phenoxy]phenyl}ethyl)-acetamide,-   N-{2-[4-(4-Chlorophenoxy)phenyl]ethyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-{2-[4-(4-Acetylphenoxy)phenyl]ethyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[4-(pyridin-3-yloxy)phenyl]ethyl}-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-(2-{4-[(6-methoxypyridin-3-yl)oxy]phenyl}ethyl)-acetamide,-   N-{2-[4-(4-Cyanophenoxy)phenyl]ethyl    }-2-(2,5-dioxoimidazolidin-4yl)-acetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[4-(4-methylphenoxy)phenyl]ethyl}-acetamide,-   2-(2,5-Dioxoimidazolidin-4yl)-N-{2-[4-(4-fluorophenoxy)phenyl]ethyl}-acetamide,-   N-(2-Biphenyl-4yl-2-hydroxy-ethyl)-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(1,1    ′-Biphenyl-4-yl)-2-methoxyethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,-   N-[2-(1,1    ′-Biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-N-methylacetamide,-   2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-phenylethynyl-piperidin-1-yl)ethyl]-acetamide,-   N-{2-[(4-Bromobenzyl)oxy]ethyl}-2-(2,5-dioxoimidazolidin-4yl)-acetamide,-   2-(1,1′-Biphenyl-4-yl)-2-oxoethyl    (2,5-dioxoimidazolidin-4-yl)acetate,    and pharmaceutically acceptable salts and solvates thereof.

It will be appreciated that the particular substituents and number ofsubstituents in the compounds of the invention are selected so as toavoid sterically undesirable combinations.

Each exemplified compound represents a particular and independent aspectof the invention.

It will be appreciated that the compounds according to the invention maycontain one or more asymmetrically substituted carbon atoms. Thepresence of one or more of these asymmetric centres (chiral centres) incompounds according to the invention can give rise to stereoisomers, andin each case the invention is to be understood to extend to all suchstereoisomers, including enantiomers and diastereomers, and mixturesincluding racemic mixtures thereof. Racemates may be separated intoindividual optically active forms using known procedures (cf. AdvancedOrganic Chemistry: 3rd Edition: author J March, p104-107) including forexample the formation of diastereomeric derivatives having convenientoptically active auxiliary species followed by separation and thencleavage of the auxiliary species.

Where optically active centres exist in the compounds of the invention,we disclose all individual optically active forms and combinations ofthese as individual specific embodiments of the invention, as well astheir corresponding racemates.

Where tautomers exist in the compounds of the invention, we disclose allindividual tautomeric forms and combinations of these as individualspecific embodiments of the invention.

The compounds of the invention may be provided as pharmaceuticallyacceptable salts or solvates. These include acid addition salts such ashydrochloride, hydrobrornide, citrate, tosylate and maleate salts andsalts formed with phosphoric and sulphuric acid. In another aspectsuitable salts are base salts such as an alkali metal salt for examplesodium or potassium, an alkaline earth metal salt for example calcium ormagnesium, or organic amine salt for example triethylamine. Examples ofsolvates include hydrates.

The compounds of formula (I) have activity as pharmaceuticals. Aspreviously outlined the compounds of the invention are metalloproteinaseinhibitors, in particular they are inhibitors of MMP12 and may be usedin the treatment of diseases or conditions mediated by MMP12 such asasthma, rhinitis, chronic obstructive pulmonary diseases (COPD),arthritis (such as rheumatoid arthritis and osteoarthritis),atherosclerosis and restenosis, cancer, invasion and metastasis,diseases involving tissue destruction, loosening of hip jointreplacements, periodontal disease, fibrotic disease, infarction andheart disease, liver and renal fibrosis, endometriosis, diseases relatedto the weakening of the extracellular matrix, heart failure, aorticaneurysms, CNS related diseases such as Alzheimer's disease and MultipleSclerosis (MS), and hematological disorders.

The compounds of the invention show a favourable selectivity profile.Whilst we do not wish to be bound by theoretical considerations, thecompounds of the invention are believed to show selective inhibition forany one of the above indications relative to any MMPl inhibitoryactivity, by way of non-limiting example they may show 100-1000 foldselectivity over any MMP1 inhibitory activity.

Accordingly, the present invention provides a compound of formula (I),or a pharmaceutically acceptable salt or solvate thereof, ashereinbefore defined for use in therapy.

In another aspect, the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,as hereinbefore defmed in the manufacture of a medicament for use intherapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention further provides a method of treating a disease orcondition mediated by MMP12 which comprises administering to a patient atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof as hereinbeforedefined.

The invention also provides a method of treating an obstructive airwaysdisease (e.g. asthma or COPD) which comprises administering to a patienta therapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof as hereinbeforedefined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. The daily dosage ofthe compound of formula (I)/salt/solvate (active ingredient) may be inthe range from 0.001 mg/kg to 75 mg/kg, in particular from 0.5 mg/kg to30 mg/kg. This daily dose may be given in divided doses as necessary.Typically unit dosage forms w contain about 1 mg to 500 mg of a compoundof this invention.

The compounds of formula (I) and pharmaceutically acceptable salts andsolvates thereof may be used on their own but will generally beadministered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (per cent by weight), morepreferably from 0.10 to 70% w, of active ingredient, and, from 1 to99.95% w, more preferably from 30 to 99.90% w, of a pharmaceuticallyacceptable adjuvant, diluent or carrier, all percentages by weight beingbased on total composition.

Thus, the present invention also provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof as hereinbefore defined in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof as hereinbefore defined with a pharmaceutically acceptableadjuvant, diluent or carrier.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease or condition that it is desired totreat, for example by oral, topical, parenteral, buccal, nasal, vaginalor rectal adminstration or by inhalation. For these purposes thecompounds of this invention may be formulated by means known in the artinto the form of, for example, tablets, capsules, aqueous or oilysolutions, suspensions, emulsions, creams, ointments, gels, nasalsprays, suppositories, finely divided powders or aerosols forinhalation, and for parenteral use (including intravenous, intramuscularor infusion) sterile aqueous or oily solutions or suspensions or sterileemulsions.

In addition to the compounds of the present invention the pharmaceuticalcomposition of this invention may also contain, or be co-administered(simultaneously or sequentially) with, one or more pharmacologicalagents of value in treating one or more diseases or conditions referredto hereinabove such as “Symbicort” (trade mark) product.

Preparation of the Compounds of the Invention

The present invention further provides a process for the preparation ofa compound of formula (I) or a pharmaceutically acceptable salt orsolvate thereof as defined above which comprises,

(a) when X represents an oxygen atom or a group NR⁴, reacting a compoundof formula

wherein X¹ represents an oxygen atom or a group NR⁴ and L, G² and R⁴ areas defined in formula (I), with an activated carboxylic acid of formula

wherein Y, Z¹, Z², R¹, R², and R³ areas defined in formula (I); or

(b) when X represents CH₂, reacting an activated carboxylic acid offormula (IV) as defined in (a) above with methoxymethylamine or a saltthereof (e.g. hydrochloride salt) followed by reaction with a Grignardreagent of formula

wherein Hal represents a halogen atom such as chlorine or bromine and Land G² are as defined in formula (I); or

(c) when X represents CH₂, reacting a compound of formula

wherein Y, Z¹, Z², R¹, R² and R³ are as defined in formula (C), with acompound of formula

wherein LG¹ represents a leaving group such as halogen or sulphonate(e.g. methylsulphonate or toluenesulphonate) and L and G² are as definedin formula (I), in the presence of a strong base (e.g. sodium hydride orlithium diisopropylamide); and optionally after (a), (b) or (c) forminga pharmaceutically acceptable salt or solvate.

In process (a), the reaction between the compounds of formulae (m) and(IV) represents a simple amide or ester coupling well known to thoseskilled in the art. The carboxylic acid of formula (IV) must beactivated in some way, for example as the acid halide, anhydride, acylurea or acyl derivative of N-hydroxysuccinimide. For a generaldescription of the preparation of amides and esters see, for example,Carey, F. A. and Sundberg, J., Advanced Organic Chemistry, 3rd Edition,pp 144-152, 1990.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of the invention may involve, at various stages, the additionand removal of one or more protecting groups.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 3rdedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1999).

Compounds of formulae (III), (IV), (V), (VI) and (VII) are eithercommercially available, are known in the literature or may be preparedusing known techniques.

For example, compounds of formula (IV) in which R¹ represents a hydrogenatom, Y represents NH and Z¹ and Z² both represent oxygen may beprepared accoding to the reaction scheme below:

Alternatively, compounds of formula (IV) in which R¹ represents ahydrogen atom, Y represents NH, Z¹ represents sulphur and Z² representoxygen may be prepared by reacting Intermediate 1 above withthiocarbamic acid (H₂N—C(S)—OH) and sodium cyanide in the presence of asolvent mixture of ethanol and water, e.g. as described in J. Chem.Soc., 1959, page 396.

Other methods are available for preparing compounds of formula (IV). Forexample, a wide range of α-amino acids are useful as synthons todioxo-imidazolidines and oxo-thioxo-imidazolidines. It is well knownthat salts of cyanic acid, urea, or thiocyanic acid together with anammonium salt react with α-amino acids to form these heterocycles(Anteunis, M. J. O.; Spiessens, L.; Witte, M. De; Callens, R.; Reyniers,Bull. Soc. Chim. Belg., EN, 96, 6, 1987, 459-466; Dakin; Am. Chem. J.,44, 1910, 49; Haurowitz et al., J. Biol. Chem., 224, 1957).

Several suitable dioxo-imidazolidine and oxo-thioxo-imidazolidine acidsare commercially available or are described in the literature asindicated below (unless otherwise stated, the numbers in brackets areCAS registry numbers):

-   (2,5-Dioxo-imidazolidin-4-yl)-acetic acid (5427-26-9, 26184-52-1,    26184-53-2, 67337-71-7);-   (3-Methyl-2,5-dioxo-imidazolidin-4-yl)-acetic acid (26972-46-3);-   5-Oxo-2-thioxo-imidazolidin-4-yl)-acetic acid (41679-36-1,    61160-00-7);-   (2,5-Dioxo-4-phenyl-imidazolidin-4-yl)-acetic acid (62985-01-7);-   (4-Methyl-2,5-dioxo-imidazolidin-4yl)-acetic acid (beilstein    registry number 145446);-   4-Imidazolidineacetic acid, 4-(hydroxymethyl)-2,5-dioxo-, (4R)-(9CI)    (391870-39-6);-   4-Imidazolidineacetic acid, 4-(4-chlorophenyl)-2,5-dioxo-(9CI)    (250352-11-5);-   4-Imidazolidineacetic acid, α-methyl-2,5-dioxo-(9CI) (184681-52-5);-   1,3-Diazaspiro[4.4]nonane-6-carboxylic acid, 2,4-dioxo-, cis-(9CI)    (147676-21-9);-   1,3-Diazaspiro[4.5]decane-6-carboxylic acid, 2,4-dioxo-(7CI, 8CI)    (947-104);-   1,3-Diazaspiro[4.4]nonane-6-carboxylic acid, 2-oxo-4-thioxo-(9CI)    (197315-95-0);-   4-Imidazolidineacetic acid, 5-oxo-2-thioxo-(9CI) (41679-36-1);-   4,4-Imidazolidinediacetic acid, 2,5-dioxo-(8CI, 9CI) (5624-17-9);    and-   4-Imidazolidineacetic acid, 4-hydroxy-2,5-dioxo-(9CI) (78703-76-1).

The present invention will now be further explained by reference to thefollowing illustrative examples.

General Procedures

¹HNMR and ¹³CNMR were recorded on a Varian^(unity) Inova 400 MHz or aVarian Mercury-VX 300 MHz instrument. The central peaks of chloroform-d(δ_(H) 7.27ppm), dimethylsulfoxide-d₆ (δ_(H) 2.50 ppm) or methanol-d₄(δ_(H) 3.31 ppm) where used as internal references. Low-resolution massspectra were obtained on an Agilent 100 LC-MS system equipped with anAPCI ionisation chamber. Column chromatography was carried out usingsilica gel (0.063-0.2 mm) (Merck). Unless stated otherwise, startingmaterials were commercially available. All solvents and commercialreagents were laboratory grade and used as received. Abbreviations: NMP:1-methyl-2-pyrollidinone TFA: trifluoroacetic acid HOBT:1-hydroxybenzotriazole PdCl₂ (dppf):bis(diphenylphosphino)ferrocene-palladium(II)chloride dichloromethanecomplex THF: tetrahydrofuran BOC: tert-butoxycarbonyl EtOH: ethanolEtOAc: ethyl acetate TLC: thin layer chromatography DMSO: dimethylsulphoxide PEG: polyethylene glycol

EXAMPLES

A. General Procedure for Preparation of2-(2.5-Dioxo-imidazolidin-4-yl)-acetamides

I. Preparation of Non-Commercial Amines

2-(4-Bromo-phenyl)-ethylamine (2mmol, 400 mg) was dissolved in 4 mL THF(dry, mol sieves) and di-tert-butyl dicarbonate (1.2 eq 2.4 mmol 520 mg)was added slowly. The reaction mixture was stirred in room temperaturefor 1 hour before it was diluted with 100 mL ethyl acetate and washedwith 100 mL sat. NaHCO₃/aq. The organic phase was dried over Na₂SO₄,filtrated and evaporated to dryness. The BOC-protected amine wasdissolved in a mixture of 10 mL toluene, 2.5 mL ethanol and 2.5 mL 2MNa₂CO₃/aq. PdCl₂(dppf) (0.03 eq, 50 mg) was added together with acorresponding boronic acid (1.05 eq, 2.1 mmol). The solution wasdegassed with nitrogen and the vessel was sealed before it was stirredovernight at 80° C. The reaction mixture was diluted with 50 mL tolueneand 50 mL water. After mixing, the organic layer was transferreddirectly on to a silica column and purified by chromatography(toluene-ethylacetate). To remove the protecting group the compound wasstirred in a mixture of 5 mL conc. HCl in 10 mL THF for 30 min. Thesolution was neutralised with 1M NaOH/aq and extracted withdichloromethane (2×). The combined organic layers was dried over Na₂SO₄,filtrated and evaporated to dryness. The amines were used in the amidesynthesis without any further purification.II. Coupling of Amines to 5 Hydantoin Acetic Acid:—Amide Synthesis

600 μL of a 0.15 solution in NMP of 5-hydantoin acetic acid was mixedwith 98 mg of polystyrene-bound carbodilmide resin (loading 1.28mmol/g). 340 μL of a 0.3M solution of HOBT in NMP was added to themixture and vortexed for 10 minutes before 200 μL of a 0.3M solution inNMP of the corresponding amine was added. The reaction mixtures werevortexed overnight at room temperature in sealed vessels. Resin wasremoved by filtration and the solution was evaporated to dryness. Theproducts were purified on semiprep-HPLC C₁₈-column (H₂O:CH₃CN, 0.1%TFAbuffer, gradient 10% to 95% CH₃CN, 10 min).

The following 2-(2,5-Dioxo-imidazolidin-4-yl)-acetamides were preparedaccording to the general procedure A outlined above.

Example 12-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-fluoro-biphenyt-4-yl)-ethyl]-acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.56 (1H, s); 8.07 (1H, t); 7.71-7.65 (2H,m); 7.59-7.55 (2H, m); 7.32-7.24 (4H, m); 4.23-4.19 (1H, m); 3.35-3.26(2H, m); 2.75 (2H, t) 2.56-2.37(2H, m) APCI-MS m/z: 356.4 [MH⁺]

Example 2N-[2-(4′-Cyano-biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.56 (1H, s); 8.07 (1H, t); 7.92-7.84 (4H,m); 7.79 (1H, s); 7.69 (2H, d); 7.35 (2H, d); 4.21(1H, t); 3.37-3.27(2H, m); 2.78 (2H, t) 2.57-2.36(2H, m) APCI-MS m/z: 363.4 [MH⁺]

Example 32-(2,5-Dioxoimidazolidin-4-yl)-N-(2-phenyl-cyclopropyl)-acetamide

APCI-MS m/z: 274.3 [MH⁺]

Example 4N-[2-(4-Chlorophenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 296.3 [MH⁺]

Example 5N-(2-Biphenyl-4-yl-ethyl)-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 338.4 [MH⁺]

Example 62-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(7-methyl-1H-indol-3-yl)ethyl]acetamide

APCI-MS m/z: 315.3 [MH⁺]

EXAMPLE 72-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-phenoxyphenyl)ethyl]-acetamide

APCI-MS m/z: 354.4 [MH⁺]

Example 82-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-fluorophenyl)ethyl]-acetamide

APCI-MS m/z: 280.3 [MH⁺]

Example 9N-[2-(4-Bromophenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 340.3; 342.3 [MH⁺]

Example 10N-[2-(2,4-Dichlorophenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 330.3; 332.3[MH⁺]

Example 11N-[2-(3′-Chloro-biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 372.4 [MH⁺]

Example 12N-[2-(4′-Benloxy-biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 444.5 [MH⁺]

Example 132-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-thiophen-3-yl-phenyl)ethyl]-acetamide

APCI-MS m/z: 344.3 [MH⁺]

Example 142-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-thiophen-2-yl-phenyl)ethyl]-acetamide

APCI-MS m/z: 344.3 [MH⁺]

Example 15N-[2-(4′-Chloro-biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 372.3 [MH⁺]

Example 162-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-methylsulfanyl-biphenyl-4-yl)ethyl]-acetamide

APCI-MS m/z: 384.4 [MH⁺]

Example 172-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(3′-nitro-biphenyl-4-yl)ethyl]-acetamide

APCI-MS m/z: 383.4 [MH⁺]

Example 182-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-methyl-biphenyl-4-yl)ethyl]-acetamide

APCI-MS m/z: 352.4 [MH⁺]

Example 19N-[2-(3′-Acetylamino-biphenyl-4-yl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 395.4 [MH⁺]

Example 202-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-naphthalen-2yl-phenyl)ethyl]-acetde

APCI-MS m/z: 388.4 [MH⁺]

Example 21N-[2-(3′,5′-Dichloro-biphenyl-4-yl)ethyl]2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 406.3; 408.4 [MH⁺]

Example 222-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(3′-methyl-biphenyl-4-yl)ethyl]-acetamide

APCI-MS m/z: 352.4 [MH⁺]

Example 23N-[2-(4-Benzofuran-2-yl-phenyl)ethyl]-2-(2,5dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 378.4 [MH⁺]

Example 242-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(3′-methoxy-biphenyl-4-yl)ethyl]-acetamide

APCI-MS m/z: 368.3 [MH⁺]

Example 252-(2,5-Dioxoimidazolidin-4-yl)-N-(2-[1,1′;4′,1″]terphenyl-4-ylethyl)-acetamide

APCI-MS m/z: 414.4 [MH⁺]

Example 26N-[2-(4′-Acetyl-biphenyl-4-yl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 380.4 [MH⁺]

Example 27N-[2-(4-Benzo[b]thiophen-2-yl-phenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 394.4 [MH⁺]

Example 28N-[2-(4′-Cyanomethyl-biphenyl-4-yl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 377.4 MH⁺]

Example 292-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-pyridin-3-yl-phenyl)ethyl]-acetamide

APCI-MS m/z: 339.4 [MH⁺]

Example 302-(2,5-Dioxoimidazolidin-4yl)-N-{2-[4-(1H-pyrrol-2-yl)phenyl]ethyl}-acetamide

APCI-MS m/z: 327.4 [MH⁺]

Example 312-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-furan-3-yl-phenyl)ethyl]-acetamide

APCI-MS m/z: 328.4 [MH⁺]

Example 322-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-furan-2-yl-phenyl)ethyl]-acetamide

APCI-MS m/z: 328.4 [MH⁺]

Example 332-(2,5-Dioxomidazolidin-4yl)-N-(2-thiophen-2-yl-ethyl)-acetamide

APCI-MS m/z: 268.3 [MH⁺]

Example 34N-[2-(4-tert-Butylphenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 318.4 [MH⁺]

Example 35N-[2-(4-Chlorophenyl)-1-methylethyl]-2-(2,5-dioxoimidazolidin-4yl)acetamide

¹H NMR (400MHz,DMSO d₆): δ 10.55(1H, d); 7.88 (1H, dd);7.76 (1H, d);7.33-7.31 (2H, m); 7.21-7.19 (2H, m); 4.19-4.16 (1H, m); 3.94-3.88 (1H,m); 2.77-2.32 (4H, m); 0.99 (3H, dd) APCI-MS m/z: 310.3 [MH³⁰ ]

Example 36N-{[1-(4-Chlorophenyl)cyclopropyl]methyl}-2-(2,5-dioxoimidazolidin-4-yl)acetamide

¹H NMR (400MHz,DMSO-d₆): δ 10.53(1H, d); 7.95 (1H, t); 7.73 (1H, s);7.33-7.25 (4H, m); 4.18-4.15 (1H, m); 3.39-3.22 (2H, m); 2.54-2.37 (2H,m); 0.90-0.88 (2H, m); 0.76-0.73 (2H, m) APCI-MS m/z: 322.3 [MH⁺]

Example 37N-2,3-Dihydro-1-inden-2-yl-2-(2,5-dioxoimidazolidin-4-yl)acetamide

¹H NMR (400MHz,DMSO-d₆): δ 10.54(1H, d); 8.24 (1H, d); 7.82 (1H, s);7.22-7.20(2H, m); 7.16-7.13 (2H, m); 4.47-4.42 (1H, m); 4.22-4.19(1H,m); 3.19-3.12(2H, m); 2.80-2.72 (2H, m); 2.54-2.36 (2H, m) APCI-MS m/z:274.2 [MH⁺]

B. General Procedure for Preparation of(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamides

I. tert-butyl(4-methyl-2,5-dioxoimidazolidin-4-yl)acetate

Tert-butyl acetoacetate (200 mg; 1.3 mmol), KCN (165 mg; 2.5 mmol) and(NH₄)₂CO₃ (605 mg; 6.3 mmol) was suspended in EtOH (2 mL) and H₂O (2 mL)in a sealed tube. The mixture was heated to 85-90 ° C. and a solutionwas obtained, the heating was continued over night. The resultingslightly yellow solution was allowed to cool to roomtemperature and aprecipitate was formed. The mixture was neutralised with 5% NaHSO₄ (aq)and diluted with H₂O (30 mL). The slurry was extracted with EtOAc (2×50mL). The organic phase was dried (Na₂SO₄), filtered and evaporated togive the title compound as a colourless solid. Obtained 210 mg (73%yield).

¹H-NMR(DMSO-D6):δ 10.58 (1H, s), 7.91 (1H, s), 2.76+2.39 (1H each, ABq),1.35 (9H, s), 1.23 (3H, s) ppm.II. (4-methyl-2,5-dioxoimidazolidin-4yl)-acetic acid

Deprotection afforded the title compound.

The following (4-methyl-2,5-dioxoimidazolidin-4-yl)acetamiides wereprepared by coupling of the appropiate amine to(4-methyl-2,5doxoimdazolidin-4-yl)-acetic acid by the general procedureA above.

Example 38N-[2-(4-Chlorophenyl)ethyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.42(1H, s); 7.94(1H, t); 7.35(1H, s);7.35-7.31 (2H, m); 7.24-7.21 (2H, m) ; 3.21 (2H, q); 2,67 (2H, dd);2.53-2.36 (2H, m); 1.21 (3H, s) APCI-MS m/z: 310.3 [MH⁺]

Example 39N-[2-(4-Chlorophenyl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.42 (1H,m); 7.89-7.86 (1H, m); 7.65-7.64(1H, m); 7.35-7.32 (2H, m); 7.24-7.22 (2H, m); 3.19-3.09 (2H, m);2.87-2.77 (1H, m); 2.53-2.37 (2H, m); 1.19 (3H, d); 1.14 (3H, d) APCI-MSm/z: 324.4 [MH⁺]

Example 40N-[2-(4′-Cyano-1,1′-biphenyl-4-yl)ethyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamideAPCI-MS m/z: 377.3 [MH⁺] Example 41N-[2-(4′-Fluoro-1,1′-biphenyl-4-yl)ethyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.42 (1H,s); 7.99 (1H, t); 7.97-7.65 (3H,m); 7.56 (2H, d); 7.30-7.24 (4H, m); 3.28-3.23 (2H, m); 2.73-2.70 (2H,m); 2.54-2.39 (2H, m); 1.22 (3H, s) APCI-MS m/z: 370.4 [MH⁺]

Example 422-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-fluoro-1,1′-biphenyl-4-yl)propyl]-acetamide

a) 2-(4-Bromo-phenyl)-propylamine

2-Phenyl-propylamine (1 g, 7.4 mmol) was dissolved in n-hexane (30 mL)and HBr/aq (5 drops) together with ZnBr on silica (1.75 mmol/g, 1 g).Br₂ (14.8 mmol, 900 μL) was slowly added and the slurry was stirred overnight. The slurry was diluted with ethyl acetate (300 mL) and washedwith 2M Na₂CO₃ (300 mL). The organic phase was dried over Na₂SO₄,filtered and evaporated to dryness. Purification and separation ofregioisomers was done on semi prep-HPLC C₁₈-column (H₂O CH₃CN, 1% NH₄OAcbuffer, gradient 10% to 60% CH₃CN, 30 min). Yield 23%

b) [2-(4-Bromo-phenyl)-propyl]-carbamic acid tert-butyl ester

2-(4-Bromo-phenyl)-propylamine (18.7 mmol, 4g) was dissolved in 50 mLTHF (dry, mol sieves) and di-tert-butyl dicarbonate (1.2 eq 23 mmol 5 g)was added slowly. The reaction mixture was stirred at room temperaturefor 1 hour before it was diluted with 300 mL ethyl acetate and washedwith 300 mL sat. NaHCO₃/aq. The organic phase was dried over Na₂SO₄,filtrated and evaporated to dryness.

c) [2-(4′-Fluoro-biphenyl-4-yl)-propyl]-carbamic acid tert-butyl ester

The BOC-protected amine obtained in b) above was dissolved in a mixtureof 10 mL toluene, 2.5 mL ethanol and 2.5 mL 2M Na₂CO₃/aq. PdCl₂(dppf)(0.03 eq, 50 mg) and 4-fluorobenzeneboronic acid (1.05eq, 2.1mmol) wereadded. The solution was degassed with nitrogen and the vessel was sealedbefore it was stirred overnight at 80° C. The reaction mixture wasdiluted with 50 mL toluene and 50 mL water. After mixing, the organiclayer was transferred directly on to a silica column and purified bychromatography (toluene-ethyl acetate).

d) 2-(4′-Fluoro-biphenyl-4-yl)-propylamine

To remove the protecting group the compound obtained in c) above wasstirred in a mixture of 5 mL conc. HCl in 10 mL THF for 30 min. Thesolution was neutralised with 1M NaOH/aq and extracted withdichloromethane (2×). The combined organic layers was dried over Na₂SO₄,filtrated and evaporated to dryness.

e)2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-fluoro-1,1′-biphenyl-4-yl)propyl]-acetamide

600μL of a 0.15M solution in NMP of 5-hydantoin acetic acid was mixedwith 98 mg of polystyrene-bound caibodiimide resin (loading 1.28mmol/g). 340 μL of a 0.3M solution of HOBT in NMP was added to themixture and vortexed for 10 minutes before 200 μL of a 0.3M solution inNMP of 2-(4′-fluoro-biphenyl-4-yl)-propylamine was added. The reactionmixture was vortexed overnight at room temperature in a sealed vessel.Resin was removed by filtration and the solution was evaporated todryness. The product was purified on semi prep-HPLC C₁₈-column(H₂O:CH₃CN, 0.1% TFA buffer, gradient 10% to 95% CH₃CN, 10 min).

¹H NMR (400 MHz,DMSO-d₆): δ 10.55 (s, 1H), 8.00 (s, 1H), 7.76 (s, 1H),7.68 (dd, J=8.7, 5.5 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.32-7.25 (m, 4H),4.22-4.17 (m, 1H), 3.23 (dd, J=20.7, 6.3 Hz, 2H), 2.92 (q, J=7.0 Hz,1H), 2.57-2.35 (m, 2H), 1.21 (d, J=7.1 Hz, 3H). APCI-MS m/z: 370.2 [MH⁺]

The following compounds were prepared according to methods analogous toExample 42 above.

Example 43N-[(1S,2R)-2-(4′-Methoxybiphenyl-4-yl)cyclopropyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.44 (d, J=7.6 Hz, 1H), 8.18 (dd, J=6.8,4.3Hz, 1H), 7.73 (s, 1H), 7.54 (d, J=8.9 Hz, 2H), 7.48 (d, J=8.3 Hz, 2H),7.13 (dd, J=8.3,2.8 Hz, 2H), 6.99 (d, J=8.9 Hz, 2H), 3.77 (s, 3H),2.79-2.73 (m, 1H), 2.56-2.46 (m, 1H), 2.37 (d, J=15.2 Hz, 1H), 1.90 (dt,J=6.1, 3.1 Hz, 1H), 1.23 (s, 3H), 1.17-1.09 (m, 2H). APCI-MS m/z: 394.3[MH⁺]

Example 44N-[(1S,2R)-2-(4′-Cyanobiphenyl-4-yl)cyclopropyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 389.3 [MH⁺]

Example 45N-[(1S,2R)-2-(4′-Acetylbiphenyl-4-yl)cyclopropyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.44 (d, J=8.3 Hz, 1H), 8.20 (dd, J=7.3,4.3 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.78.(d, J=8.5 Hz, 2H), 7.73 (s,1H), 7.63 (d, J=8.3 Hz, 2H), 7.21 (dd, J=8.3, 3.1 Hz, 2H), 2.80 (dd,J=7.4, 4.0 Hz, 1H), 2.59 (s, 3H), 2.56-2.35 (m, 2H), 1.95 (tq, J=6.2,3.2 Hz, 1H), 1.23 (s, 3H), 1.22-1.13 (m, 2H). APCI-MS m/z: 406.3[MH⁺]

Example 46N-{(1S,2R)-2-[4′-(Acetylamino)biphenyl-4-yl]cyclopropyl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamideAPCI-MS m/z: 421.3[MH⁺] Example 47N-[2-(4′-Cyanobiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.43 (s, 1H), 7.95-7.85 (m, 5H), 7.67 (dd,J=14.2, 8.5 Hz, 3H), 7.36 (dd, J=8.3, 1.7 Hz, 2H), 1.19 (s, 3H), 1.21(d, J=3.9 Hz, 3H), 3.20 (sextet, J=6.8 Hz, 2H), 2.94-2.87 (m, H),2.54-2.39 (m, 2H). APCI-MS m/z: 391.3[MH⁺]

Example 482-(2,5-Dioxoimidazoldin-4-yl)-N-[2-(3′-methoxybiphenyl-4-yl)ethyl]-acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.56 (s, 1H), 8.07 (t, J=5.5 Hz,1H), 7.80(s, 1H), 7.59 (d, J=8.1 Hz, 2H), 7.36 (t, J=8.0Hz, 1H), 7.30 (d, J=8.2Hz, 2H), 7.20 (d, J=7.7 Hz, 1H), 7.16 (t, J=2.0 Hz, 1H), 6.91 (dd,J=8.1, 2.3 Hz, 1H), 4.24-4.20 (m, 1H), 3.82 (s, 3H), 3.34-3.26 (m, 2H),2.75 (t, J=7.3 Hz, 2H), 2.57-2.37 (m, 2H ). APCI-MS m/z: 368.2[MH⁺]

Example 49N-[2-(4′-Cyano-3′-methylbiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.41 (s, 1H), 7.92 (t, J=5.6Hz, 1H), 7.81(d, J=8.1 Hz, 1H), 7.77 (s, 1H), 7.69-7.62 (m, 4H), 7.34 (dd, J=8.3, 1.7Hz, 2H), 3.18 (t, J=6.5 Hz, 2H), 2.89 (dd, J=6.9, 2.6 Hz, 1H), 1.18 (s,3H), 1.20 (d, J=4.1 Hz, 3H), 2.53 (s, 3H), 2.51-2.38 (m, 2H). APCI-MSm/z: 405.3[MH⁺]

Example 502-(2,5-Dioxoimidazolidin-4-yl)-N-methyl-N-(2-phenylethyl)-acetamide

APCI-MS m/z: 276.2 [MH⁺]

Example 51N-[1-(4-Chlorophenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 296.1 [MH⁺]

Example 522-(2,5-Dioxoimidazolidin-4-yl)-N-(2-hydroxy-1-methyl-2-phenylethyl)-acetamide

APCI-MS m/z: 292.3[MH⁺]

Example 53 N-{2-[4-(1,3-Benzodioxol-5-yl)phenyl]propyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 396.5 [MH⁺]

Example 542-(2,5-Dioxoimidazoldin-4-yl)-N-[2-(3′-methoxybiphenyl-4-yl)propyl]-acetamide

APCI-MS m/z: 382.4 [MH⁺]

Example 55N-{2-[3′-(Acetylamino)biphenyl-4-yl]propyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 409.5 [MH⁺]

Example 56N-[2-(3′-Acetylbiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 394.4 [MH⁺]

Example 57N-[2-(4′-Acetylbiphenyl-4yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 394.5 [MH⁺]

Example 58N-{2-[4-(1-Benzothien-2-yl)phenyl]propyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 408.4 [MH⁺]

Example 59N-[2-(3′-Cyanobiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 377.4 [MH⁺]

Example 60N-[2-(4′-Cyanobiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 377.4 [MH⁺]

Example 612-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-fluoro-3′-methylbiphenyl-4-yl)propyl]-acetamide

APCI-MS m/z: 384.4 [MH⁺]

Example 622-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[3′-(methylthio)biphenyl-4-yl]propyl}-acetamideAPCI-MS m/z: 398.4 MH⁺] Example 632-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[4-(6-methoxypyridin-3-yl)phenyl]propyl}-acetamide

APCI-MS m/z: 383.4 [MH⁺]

Example 642-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-methoxy-3′-methylbiphenyl-4-yl)propyl]-acetamide

APCI-MS m/z: 396.5 [MH⁺]

Example 65N-{2[4-(2,3-Dihydro-1-benzofuran-5-yl)phenyl]propyl}-2-(2,5-dioxoimidazoldin-4-yl)-acetamide

APCI-MS m/z: 394.5 [MH⁺]

Example 662-(2,5-Dioxoimidazoldin-4-yl)-N-{2-[3′-(trifluoromethoxy)biphenyl-4-yl]propyl}-acetamide

APCI-MS m/z: 436.5 [MH⁺]

Example 67N-[2-(3′,4′-Dimethoxybiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazoldin-4-yl)-acetamide

APCI-MS m/z: 412.5 [MH⁺]

Example 682-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-quinolin-3-ylphenyl)propyl]-acetamide

APCI-MS m/z: 403.5 [MH⁺]

Example 69N-[2-(4′-Cyano-3′-methylbiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 391.5 [MH⁺]

Example 70 N-[5-(1,3-Benzodioxol-5-yl)-2,3,dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 394.4 [MH⁺]

Example 712-(2,5-Dioxoimidazoidin-4-yl)-N-[5-(3-methoxyphenyl)-2,3-dihydro-1H-inden-2-yl]-acetamide

APCI-MS m/z: 380.4 [MH⁺]

Example 72N-{5-[3-(Acetylamino)phenyl]-2,3-dihydro-1H-inden-2-yl}-2-(2,5-dioxoimidazoldin-4-yl)-acetamide

APCI-MS m/z: 407.5 [MH⁺]

Example 73N-[5-(3-Acetylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 392.4 [MH⁺]

Example 74N-[5-(4-Acetylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 392.5 [MH⁺]

Example 75N-[5-(1-Benzothien-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 406.4 [MH⁺]

Example 76N-[5-(3-Cyanophenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 375.4 [MH⁺]

Example 77N-[5-(4-Cyanophenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 375.4 [MH⁺]

Example 782-(2,5-Dioxoimidazolidin-4-yl)-N-[5-(4-fluoro-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-acetamide

APCI-MS m/z: 382.4 [MH⁺]

Example 792-(2,5-Dioxoimidazolidin-4-yl)-N-{5-[3-(methylthio)phenyl]-2,3-dihydro-1H-inden-2-yl}-acetamide

APCI-MS m/z: 396.4 [MH⁺]

Example 802-(2,5-Dioxoimidazolidin-4-yl)-N-[5-(6-methoxypyridin-3-yl)-2,3-dihydro-1H-inden-2-yl]-acetamide

APCI-MS m/z: 381.4 [MH⁺]

Example 812-(2,5-Dioxoimidazoldin-4-yl)-N-[5-(4-methoxy-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-acetamide

APCI-MS m/z: 394.5 [MH⁺]

Example 82N-[5-(2,3-Dihydro-1-benzofuran-5-yl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)acetamide

APCI-MS m/z: 392.4 [MH⁺]

Example 83N-[5-(3,4-Dimethoxyphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazoldin-4-yl)-acetamide

APCI-MS m/z: 410.5 [MH⁺]

Example 84N-[2-(4′-Fluorobiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 384.5 [MH⁺]

Example 85N-{2-[4-(1,3-Benzodioxol-5-yl)phenyl]propyl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 410.5 [MH⁺]

Example 86N-[2-(3′-Methoxybiphenyl-4-yl)propyl]-2-(4methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 396.5 [MH⁺]

Example 87N-{2-[4-(1-Benzothien-2-yl)phenyl]propyl}-2-(4-methyl-2,5dioxoimdazolidin-4-yl)-acetamide

APCI-MS m/z: 422.5 [MH⁺]

Example 88N-[2-(3′-Cyanobiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 391.5 [MH⁺]

Example 89N-[2-(4′-Fluoro-3′-methylbiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 398.5 [MH⁺]

Example 902-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-{2-[3′-(methylthio)biphenyl-4-yl]propyl}-acetamide

APCI-MS m/z: 412.5 [MH⁺]

Example 91N-{2-[4-(6-Methoxypyridin-3-yl)phenyl]propyl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 397.5 [MH⁺]

Example 92N-[2-(4′-Methoxy-3′-methylbiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 410.5 [MH⁺]

Example 93N-{2-[4-(2,3-Dihydro-1-benzofuran-5-yl)phenyl]propyl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 408.5 [MH⁺]

Example 942-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-{2-[3′-(trifluoromethoxy)biphenyl-4-yl]propyl}-acetamide

APCI-MS m/z: 450.5 [MH⁺]

Example 95N-[2-(3′,4′-Dimethoxybiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 426.5[MH⁺]

Example 962-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-[2-(4-quinoln-3-ylphenyl)propyl]-acetamide

APCI-MS m/z: 417.5 [MH⁺]

Example 97N-[5-(4-Fluorophenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 382.5 [MH⁺]

Example 98N-[5-(1,3-Benzodioxol-5-yl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 408.5 [MH⁺]

Example 99N-[5-(3-Methoxyphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 394.5 [MH⁺]

Example 100N-{5-[3-(Acetylamino)phenyl]-2,3-dihydro-1H-inden-2-yl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 421.5 [MH⁺]

Example 101N-[5-(3-Acetylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 406.5 [MH⁺]

Example 102N-[5-(4-Acetylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 406.5 [MH⁺]

Example 103N-[5-(1-Benzothien-2-yl)-2,3-dihydro-1H-inden-2yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 420.5 [MH⁺]

Example 104N-[5-(3-Cyanophenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 389.5 [MH⁺]

Example 105N-[5-(4-Cyanophenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 389.5 [MH⁺]

Example 106N-[5-(4-Fluoro-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 396.5 [MH⁺]

Example 1072-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-{5-[3-(methylthio)phenyl]-2,3-dihydro-1H-inden-2-yl}-acetamide

APCI-MS m/z: 410.5 MH⁺]

Example 108N-[5-(6-Methoxypyridin-3-yl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 395.5 [MH⁺]

Example 109N-[5-(4-Methoxy-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 408.5 [MH⁺]

Example 110N-[5-(2,3-Dihydro-1-benzofuran-5-yl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 406.5 [MH⁺]

Example 1112-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-{5-[3-(trifluoromethoxy)phenyl]-2,3-dihydro-1H-inden-2-yl}-acetamide

APCI-MS m/z: 448.5 [MH⁺]

Example 112N-[5-(3,4-Dimethoxyphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 424.5 [MH⁺]

Example 113N-[5-(4-Cyano-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide

APCI-MS m/z: 403.5 [MH⁺]

Example 114 2-(2,5-Dioxoimidazolidin-4-yl)-N-(2-{4-[4(trifluoromethyl)phenoxy]phenyl}ethyl)-acetamide

a) [2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester

2-(4-Hydroxyphenyl)-ethylamine (36.5 mmol, 5g) was dissolved in 100 mLTHF (dry, mol sieves) and di-tert-butyl dicarbonate (1 .2 eq 43.8 mmol,9.5 g) was added slowly. The reaction mixture was stirred at roomtemperature for 1 hour before it was diluted with 700 mL ethyl acetateand washed with 500 mL sat. NaHCO₃/aq. The organic phase was dried overNa₂SO₄. filtrated and evaporated to dryness.

b) {2-[4-(4-Trifluoromethyl-phenoxy)-phenyl]-ethyl)carbanic acidtert-butyl ester

0.5 mmol of the BOC-protected amine obtained in a) above was dissolvedin dichloromethane (5 mL) together with copper(II)acetate (0.5 mmol, 90mg), powdered 4 Å mol sieves (app. 100 mg) and4-(trifluoromethyl)benzeneboronic acid (1 mmol). After stirring thereaction mixture overnight at room temperature the slurry was filteredand purified by flash chromatography.

c) 2-[4-(4-Trifluoromethyl-phenoxy)-phenyl]-ethylamine

The BOC-group was removed by stirring the compound obtained in b) abovein hydrochloric acid/THF (0.5 mL conc. HCl/1.5 mL THF) for 2 hours atroom temperature before it was made basic by adding 10.5 mL 1M NaOH/aq.The free amine was extracted with 3×10 mL dichloromethane that was driedover Na₂SO₄, filtrated and evaporated to dryness. Yield 0.32 mmol (62%).

d)2-(2,5-Dioxoimidazolidin-4-yl)-N-(2-{4-[4-(trifluoromethyl)phenoxy]-phenyl}ethyl)-acetamide

The title compound was prepared by a method analogous to that describedin Example 42e).

¹H NMR (400 MHz,DMSO-d₆): δ 10.55 (s, 1H), 8.05 (t, J=5.6 Hz, 1H), 7.79(s, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 7.08 (dd,J=20.1, 8.5 Hz, 4H), 4.20 (dd, J=6.2, 4.8 Hz, 1H), 3.29 (q, J=6.8 Hz,2H), 2.73 (t, J=7.3 Hz, 2H), 2.57-2.36 (m, 2H). APCI-MS m/z: 422.3 [MH⁺]

The following compounds were prepared according to methods analogous toExample 114 above.

Example 1152-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[4-(4-methoxyphenoxy)phenyl]ethyl}-acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.54 (s, 1H), 8.01 (t, J=5.5 Hz, 1H), 7.77(s, 1H), 7.16 (d, J=8.6 Hz, 2H), 6.97-6.91 (m, 4H), 6.83 (d, J=8.5 Hz,2H), 4.18 (dd, J=6.2, 4.6 Hz, 1H), 3.72 (s, 3H), 3.22 (q, J=6.8 Hz, 2H),2.65 (t, J=7.4 Hz, 2H), 2.55-2.33 (m, 2H). APCI-MS m/z: 384.3 [MH⁺]

Example 1162-(2,5-Dioxoimidazolidin-4-yl)-N-(2-{4-[4-(trifluoromethoxy)phenoxy]phenyl}ethyl)-acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.55 (s, 1H), 8.04 (t, J=5.5 Hz, 1H), 7.79(s, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 7.07 (td,J=6.4, 4.0 Hz, 2H), 6.99 (d, J=8.5 Hz, 2H), 4.20 (dd, J=6.1, 4.7 Hz,1H), 3.27 (q, J=6.8 Hz, 2H), 2.71 (t, J=7.4 Hz, 2H), 2.57-2.35 (m, 2H).APCI-MS m/z: 438.3 [MH⁺]

Example 117N-{2-[4-(4-Chlorophenoxy)phenyl]ethyl}-2-(2,5-dioxoimidazoldin-4-yl)-acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.55 (s, 1H), 8.04 (t, J=5.5 Hz, 1H), 7.79(s, 1H), 7.41 (dd, J=12.4, 3.5 Hz, 2H), 7.24 (d, J=8.5 Hz, 2H),7.01-6.95 (m, 4H), 4.20 (dd, J=6.1, 4.7 Hz, 1H), 3.26 (q, J=6.8 Hz, 2H),2.70 (t, J=7.4 Hz, 2H), 2.57-2.34 (m, 2H). APCI-MS m/z: 388.3 [MH⁺]

Example 118N-{2-[4-(4-Acetylphenoxy)phenyl]ethyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

¹H NMR (400 MHz,DMSO-d₆,): δ 10.55 (s, 1H), 8.05 (t, J=5.7 Hz, 1H), 7.97(d, J=8.9 Hz, 2H), 7.80 (s, 1H), 7.29 (d, J=8.5 Hz, 2H), 7.04 (t, J=8.8Hz, 4H), 4.22-4.19 (m, 1H), 3.33-3.24 (m, 2H), 2.73 (t, J=7.2 Hz, 2H),2.58-2.35 (m, 5H). APCI-MS m/z: 396.3 [MH⁺]

Example 1192-(2,5-Dioxoimidazoldin-4-yl)-N-{2-[4-(pyridin-3-yloxy)phenyl]ethyl}-acetamideAPCI-MS m/z: 355.3 [MH⁺] Example 1202-(2,5-Dioxoimidazolidin-4-yl)-N-(2-{4-[(6-methoxypyridin-3-yl)oxy]phenyl}ethyl)-acetamide

APCI-MS m/z: 385.1 [MH⁺]

Example 121N-{2-[4-(4-Cyanophenoxy)phenyl]ethyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.57 (s, 1H), 8.05 (t, J=5.5 Hz, 1H), 7.81(d, J=8.9 Hz, 2H), 7.79 (s, 1H), 7.30 (d, J=8.5 Hz, 2H ), 7.06 (d, J=8.8Hz, 4H), 4.20 (dd, J=6.1, 4.8 Hz, 1H ), 3.28 (q, J=6.7 Hz, 2H), 2.73 (t,J=7.3 Hz, 2H), 2.56-2.36 (m, 2H). APCI-MS m/z: 379.3 [MH⁺]

Example 1222-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[4-(4-methylphenoxy)phenyl]ethyl}-acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 8.03 (t, J=5.5 Hz, 1H), 7.79(s, 1H), 7.21-7.16 (m, 4H), 6.89 (d, J=8.2 Hz, 4H), 4.20 (dd,J=6.0,4.5Hz, 1H), 3.25 (q, J=6.8 Hz, 2H), 2.68 (t, J=7.4 Hz, 2H),2.56-2.35 (m, 2H), 2.28 (s, 3H). APCI-MS m/z: 368.3 [MH⁺]

Example 1232-(2,5-Dioxoimidazoldin-4-yl)-N-{2-[4-(4-fluorophenoxy)phenyl]ethyl}-acetamide

¹H NMR (400 MHz,DMSO-d₆): δ 10.53 (s, 1H), 8.02 (t, J=5.5 Hz, 1H), 7.77(s, 1H), 7.23-7.17 (m, 4H), 7.02 (tt, J=4.5, 2.3 Hz, 2H), 6.90 (d, J=8.5Hz, 2H), 4.18 (dd, J=6.0, 4.7 Hz, 1H), 3.24 (q, J=6.8 Hz, 2H), 2.67 (t,J=7.3 Hz, 2H), 2.54-2.33 (m, 2H). APCI-MS m/z: 372.3 [MH⁺]

Example 124N-(2-Biphenyl-4-yl-2hydroxy-ethyl)-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

a) 4-Phenylphenyloxirane

4-Phenyl-(α-bromoacetophenone), 8.25 g (0.030 mol), was slurried inmethanol (150 mL). Sodium borohydride (3.80 g; 0.10 mol) was added inportions to give an exothermal is reaction and a homogeneous reactionmixture. After 20 hours, water (600 mL) was added and the mixture wasextracted with dichloromethane (500 mL). The organic phase wasevaporated to give 7.25 g of crude product. NMR analysis showed mainly a1:1 mixture of epoxide and vicinal bromo alcohol.

b) 2-Amino-1-biphenyl-4-yl-ethanol

The product mixture obtained in a) above was dissolved in THF (ca 100mL) and a large excess of concentrated ammonia and ethanol was added togive a homogeneous system. TLC analysis after 4 hours showed onlystarting materials. A slight increase in temperature gave scarceimprovement and the mixture was finally heated to 70° C. in a sealedvessel for 20 hours. TLC analysis showed absence of starting materialsand NMR analysis showec a complex mixture of products. The solvents wereevaporated and dichloromethane (150 mL) was added to give a precipitate.The mixture was filtered and the solid, about 3.8 g, and filtrate wasanalysed with TLC and NMR. Analyses showed mixtures of products butwith, possibly, expected product in the solid phase. A sample of thesolid (1.04 g) was purified by silica gel chromatography (200 mL) usingdichloromethane/methanol/concentrated ammonia (90+10+1) as eluant.Evaporation of pure fractions gave 0.62 g of the sub-titled compound.

N-(2-Biphenyl-4-yl-2-hydroxy-ethyl)-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

The title compound was prepared by a method analogous to that describedin Example 42e).

¹H NMR (400 MHz,DMSO-d₆): δ 10.57 (s, 1H), 8.10 (q, J=5.8 Hz, 1H), 7.79(s, 1H), 7.64 (t, J=8.5 Hz, 4H), 7.45 (q, J=7.7 Hz, 4H), 7.35 (t, J=7.3Hz, 1H), 5.49 (s, 1H), 4.66 (t, J=3.7 Hz, 1H), 4.26-4.17 (m, 1H),3.20-3.09 (m, 1H), 2.59 (dt, J=15.5, 3.5 Hz, 1H), 2.52-2.39 (m, 2H).APCI-MS m/z: 336.3 [MH⁺]

Example 125N-[2-(1,1′-Biphenyl-4-yl)-2-methoxyethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

a) 4-(2-Amino-1-methoxyethyl)-biphenyl

4-Vinyl-biphenyl, 1.70 g (9.4 mmol), was dissolved in methanol (10 mL)and dichloromethane (15 mL). Bromine, 0.48 mL (9.4 mmol), dissolved inmethanol (10 mL) was added over 30 minutes and TLC analysis showedcomplete reaction. The mixture was diluted with dichloromethane andadded to an aqueous solution of sodium hydrogen sulphite and the mixturewas shaken. The dichloromethane phase was washed with aqueous sodiumhydrogen carbonate and water and evaporated to give 2.81 g product. Theproduct was purified by silica gel chromatography silica gel (200 mL)with heptane/ethyl acetate (95+5) to give 1.00 g (39%) of pure4-(2-bromo-1-methoxy-ethyl)-biphenyl.4-(2-Bromo-1-methoxyethyl)-biphenyl, 1.00 g (3.64 mmol), was dissolvedin ethanol (20 mL) and added to a large excess of concentrated ammonia(20 mL). The mixture was heated to 100 ° C. in a sealed vessel for 16hours and evaporated. Chromatography on silica gel (180 mL) withdichloromethane followed by dichloromethane/ methanol/concentratedammonia (90+10+1) gave 0.47 g (61%) of the sub-titled compound.

b)N-[2-(1,1′-Biphenyl-4-yl)-2-methoxyethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

The title compound was prepared by a method analogous to that describedin Example 42e). ¹H NMR (400 MHz,DMSO-d₆): δ 10.56 (s, 1H), 8.16 (d,J=5.5 Hz, 1H), 7.78 (d, J=6.2 Hz, 1H), 7.70-7.64 (m, 4H), 7.47 (t, J=7.6Hz, 2H), 7.42-7.34 (m, 3H), 4.29 (dt, J=7.8, 5.0 Hz, 1H), 4.23-4.19 (m,1H), 3.19 (s, 3H ), 2.61-2.53 (m, 2H), 2.50-2.39 (m, 2H). APCI-MS m/z:368.2 [MH⁺]

Example 126N-[2-(1,1′-Biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-N-methylacetamide

a) (4-Phenylphenethyl)-N-methylamine

4-Phenylphenethyl amine, 0.48 g (2.4 mmol), was added to an excess ofmethyl formate (5 mL) and dichloromethane (5 mL) was added to improvesolubility. The heterogeneous reaction mixture was refluxed to give asolution within 20 hours. NMR analysis of a sample showed almostcomplete conversion to N-formyl amine. The reaction mixture wasevaporated to give 0.47 g (87%). The formyl compound, 0.47 g (2.09mmol), was dissolved in THF and 2.1 mL of 1.0 M lithium aluminiumhydride (2.1 mmol) in THF was added. TLC analysis after 20 hours showedonly starting material and 2 mL (2 mmol) of lithium aluminium hydridesolution was added. Analysis after 1 hour showed starting material andthe mixture was heated to reflux. After 1.5 hours a precipitate wasformed, the starting material consumed and tetrahydrofuran (15 ml) wasadded. The mixture was quenched by successive addition of water (0.15g), 15% aqueous sodium hydroxide (0.15 g) and water (0.45 g). Themixture was filtered and evaporated to give 0.33 g crude product. Thecrude product was purified by silica gel chromatography (100 mL) usingdichloromethane/methanol/concentrated ammonia (90+10+1) as eluant.Evaporation of pure fractions gave 78 mg (18%) of the sub-tidledcompound.

b)N-[2-(1,1′-Biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-N-methylacetamide

The title compound was prepared by a method analogous to that describedin Example 42e). APCI-MS m/z: 352.3 [MH⁺]

Example 1272-(2,5-Dioxoimidazoldin-4-yl)-N-[2-(4-phenylethynyl-piperidin-1-yl)ethyl]-acetamide

a) 4-(Phenylethynyl)piperidine

N-BOC4-ethynylpiperidin, 0.5 g (2.40 mmol), and iodobenzene, 0.29 mL(2.64 mmol) were dissolved in triethylamine (9 mL) and argon was passedthrough for a few minutes. Copper(I) iodide, 0.087 g (0.5 mmol), andbis[triphenylphosphine]palladium dichloride, 0.070 g (0.1 mmol), wereadded and the mixture was heated to 82° C. in a closed vessel for 17hours. TLC analysis indicated complete reaction. Triethylamine wasevaporated and the mixture was purified by silica gel chromatography (75mL) using heptane/ethyl acetate (4+1) as eluant. Evaporation of purefractions gave 0.497 g (73%) of N-BOC4-(phenylethynyl)piperidine. Theprotected piperidine, 0.497 g (1.74 mmol), was dissolved indichloromethane and trifluoroacetic acid (1 mL) was added. The reactionwas completed within 20 hours and the mixture was evaporated to give anoil. NMR analysis showed pure ammonium trifluoroacetate, contaminatedwith trifluoroacetic acid. The product was dissolved in dichloromethaneand extracted with aqueous sodium hydrogen carbonate and water.Evaporation of solvent gave 0.284 g (88%) of the sub-titled compound.

b) 2-[4-(Phenylethynyl)piperidin-1-yl]ethanamine

4-(Phenylethynyl)piperidine (0.5 mmol, 92 mg) was dissolved inacetonitrile (anhydrous 4 Å, 4 mL) together with bromoethylphtalimide(0.5mmol, 128 mg) and K₂CO₃ (2 mmol, 276 mg). The reaction mixture washeated to reflux for 3 hours, diluted with ethyl acetate (50 mL) andwashed with HCl/aq (1M, 50 mL). The organic phase was dried over Na₂SO₄,filtered and evaporated to dryness. The protection group was removed bystirring the compound in methylamine (33% in ethanol, 5 mL) for another3 hours. The mixture was evaporated, diluted with ethyl acetate (50 mL)and washed with NaOH (1M, 50 mL). The organic phase was dried overNa₂SO₄, filtered and evaporated to dryness. The crude product was usedwithout further purification.

c)2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-phenylethynyl-piperidin-1-yl)ethyl]-acetamide

The title compound was prepared by a method analogous to that describedin Example 42e).

¹H NMR (400 MHz,CDCl₃): δ 9.96 (s, 1H), 9.67 (s, 1H), 8.23 (s, 1H ),7.34 (dd, J=66.3, 28.1 Hz, 5H), 4.35 (s, 1H), 3.82-1.88 (m, 15H1).APCI-MS m/z: 369.3 [MH⁺]

Example 128N-{2-[(4-Bromobenzyl)oxy]ethyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

a) 2-(4-Bromo-benzyloxy)-ethylamine hydrochloride

Sodium hydride (60% in oil, 0.613 g, 15 mmol) was added in smallportions over 5 minutes to a solution of tert-butylN-(2-hydroxyethyl)-carbamate (1.771 g, 10.99 mmol), 4-bromobenzylbromide(2.676 g, 10.708 mmol) in dimethyl formarnide (50 ml). The mixture wasstirred for 2 hours at ambient temperature under argon. The mixture waspartitioned between water (250 mL), ethyl acetate (50 mL) and heptane(50 mL). The organic phase was washed two times with water (30 mL).Evaporation afforded 3.13 g of a clear oil. The oil was stirred in 2.5 MHCl in ethyl acetate (50 mL) for 2 hours. Filtering and washing withethyl acetate afforded the sub-titled compound (2.256 g, 98.1% yield).

¹HNMR (300 MHz, DMSO-d₆): δ 8.16 (3H, bs); 7.55 (2H, d); 7.36 (2H, d);4.51 (2H, s); 3.64 (2H, t); 2.99 (2H, t). APCI-MS m/z: 229.9; 231.9[MH⁺]

b)N-{2-[(4-bromobenzyl)oxy]ethyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide

The title compound was prepared by a method analogous to that describedin Example 42e).

¹H NMR (300 MHz, DMSO-d₆): δ 10.56 (1H, s); 8.08 (1H, t); 7.81 (1H, s);7.54 (1H, d); 7.30 (1H, d); 4.45 (2H, s); 4.20 (1H, m); 3.25 (2H, q);2.50 (2H, p); 2.50 (2H, m). APCI-MS m/z: 370; 372 [MH⁺]

Example 129 2-(L1,1′-Biphenyl-4-yl)-2-oxoethyl(2.5-dioxoimidazolidin-4-yl)acetate

Hydantoin acetic acid (109 mg, 0.69 mmol), 2-bromo-4′-phenylacetophenone(191 mg, 0.69 mmol) and N-ethyl-diisopropylamine (120 μl, 0.70 mmol)were stirred in dimethylformamide (5.0 mL) at 50° C. for 3 hours.Evaporation and chromatography on silica (dichloromethane/methanol:100/3) afforded 123 mg of the title compound in 50.1% yield.

¹HNMR (300 MHz, DMSO-d₆,): δ 10.68 (H, s); 8.06 (2H, d); 7.90 (1H, s);7.87 (2H, d); 7.77 (2H, d); 7.55-7.42 (3H, m); 5.55 (2H, d); 4.32 (1H,dt); 2.90 (2H, d). APCI-MS m/z: 353.1 [MH⁺]

Pharmacological Example Isolated Enzyme Assay

Recombinant human MMP12 catalytic domain may be expressed and purifiedas described by Parkar A. A. et al, (2000), Protein Expression andPurification, 20:152. The purified enzyme can be used to monitorinhibitors of activity as follows: MMP12 (50 ng/ml final concentration)is incubated for 60 minutes at room temperature with the syntheticsubstrate Mac-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH₂ in assay buffer (0.1M“Tris-HCl” (trade mark) buffer, pH 7.3 containing 0.1 M NaCl, 20 mMCaCl₂, 0.020 mM ZnCl and 0.05% (w/v) “Brij 35 ” (trade mark) detergent)in the presence (5 concentrations) or absence of inhibitors. Activity isdetermined by measuring the fluorescence at λex 320 nm and λem 405 nm.Percent inhibition is calculated as follows: % Inhibition is equal tothe [Fluorescence_(plus inhibitor)−Fluorescence_(background)] divided bythe [Fluorescence_(minus inhibitor)−Fluorescene_(background)].

For example, the following table shows the IC₅₀figures for arepresentative selection of compounds according to the invention whentested in the MMP12 enzyme assay. Human Compound of MMP12 Example No.IC₅₀ (μm) 1 0.022 2 0.007 5 0.032 14 0.006 21 0.008 22 0.015 23 0.006 240.004 26 0.017 27 0.005

1. A compound of formula (I) or a pharmaceutically acceptable salt orsolvate thereof

wherein X represents an oxygen atom or a group NR⁴ or CH₂; Y representsNH or N-methyl; Z¹ and Z² each independently represent an oxygen orsulphur atom, provided that at least one of Z¹ and Z² represents anoxygen atom; Either R¹ represents hydrogen or a group selected fromC₁-C₆ alkyl and a saturated or unsaturated 3- to 10-membered ring systemwhich may comprise at least one ring heteroatom selected from nitrogen,oxygen and sulphur, each group being optionally substituted with atleast one substituent selected from halogen, hydroxyl, cyano, carboxyl,—NR⁵R⁶, —CONR⁷R⁸, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylcarbonyl(oxy),—S(O)mC₁-C₆ alkyl where m is 0, 1 or 2, C₁-C₆ alkylsulphonylamino, C₁-C₆alkoxycarbonyl(amino), benzyloxy and a saturated or unsaturated 5- to6-membered ring which may comprise at least one ring heteroatom selectedfrom nitrogen, oxygen and sulphur, the ring in turn being optionallysubstituted with at least one substituent selected from halogen,hydroxyl, oxo, carboxyl, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl andC₁-C₆ hydroxyalkyl, R² represents hydrogen or C₁-C₆ alky and R³represents hydrogen or C₁-C₆ alkyl, or R¹ and R² together with thecarbon atoms to which they are attached form a saturated 5- to6-membered ring optionally comprising a ring heteroatom selected fromnitrogen, oxygen and sulphur, and R³ is as defined above, or R² and R³together with the carbon atom to which they are attached form asaturated 5- to 6-membered ring optionally comprising a ring heteroatomselected from nitrogen, oxygen and sulphur, and R¹ is as defined above;R⁴ represents hydrogen or C₁-C₆ alkyl; R⁵, R⁶,R⁷ and R⁸ eachindependently represent hydrogen or C₁-C₆ alkyl optionally substitutedby at least one substituent selected from hydroxyl, halogen and C₁-C₆alkoxy; L represents —CH₂C(O)— or —C(O)CH₂-, or L represents a C₂-C₆alkyl or C₂-C₆ alkynyl group optionally interrupted or terminated by atleast one moiety selected from O, NH, S, SO, SO₂ and C(O), or Lrepresents a C₃-C₆ cycloalkyl, methylC₃-C₆ cycloalkyl or C₃-C₆cycloalkylmethyl group, each of the recited groups being optionallysubstituted with at least one substituent selected from hydroxyl,halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄haloalkoxy, or L represents a C₃-C₄ alkylene chain, the ends of whichare attached to adjacent ring carbon atoms in the 5- to 1 0-memberedring system of G² to form a ring; G² represents a saturated orunsaturated 5- to 10-membered ring system which may comprise at leastone ring heteroatom selected from nitrogen, oxygen and sulphur, the ringsystem being optionally substituted with at least one substituentselected from halogen, hydroxyl, cyano, nitro, C₁-C₆ alkyl (optionallysubstituted by one or more of cyano, halogen, hydroxyl and methoxy),C₂-C₆ alkenyl, C₁-C₆ alkoxy (optionally substituted by one or morehalogen atoms), —S(O)nC₁-C₆ alkyl where n is 0, 1 or 2, C₁-C₆alkylcarbonyl(amino), C₁-C₆ alkylcarbonyloxy, phenyl, benzyloxy, —NR⁹R¹⁰and a group of formula

R⁹ and R¹⁰ each independently represent hydrogen or C₁-C₆ alkyloptionally substituted by at least one substituent selected fromhydroxyl, halogen and C₁-C₆ alkoxy; M represents a bond or —O—, —S—,—C≡C—, —CH₂O— or —OCH₂—; G³ represents an unsaturated 5- to 10-memberedring system which may comprise at least one ring heteroatom selectedfrom nitrogen, oxygen and sulphur, the ring system being optionallysubstituted with at least one substituent selected from halogen,hydroxyl, cyano, nitro, C₁-C₆ alkyl (optionally substituted by one ormore of cyano, halogen, hydroxyl and methoxy), C₂-C₆ alkenyl, C₁-C₆alkoxy (optionally substituted by one or more halogen atoms),—S(O)_(t)C₁-C₆ alkyl where t is 0, 1 or 2, C₁-C₆ alkylcarbonyl(amino),C₁-C₆ alkylcarbonyloxy, phenyl, benzyloxy and —NR¹¹R¹²; and R¹¹ and R¹²each independently represent hydrogen or C₁-C₆ alkyl optionallysubstituted by at least one substituent selected from hydroxyl, halogenand C₁-C₆ alkoxy.
 2. A compound according to claim 1, wherein Xrepresents a group NR⁴.
 3. A compound according to claim 2, wherein R⁴represents hydrogen.
 4. A compound according to claim 1, wherein Yrepresents NH.
 5. A compound according to claim 1, wherein Z¹ and Z²both represent an oxygen atom.
 6. A compound according to claim 1,wherein L represents a C₂-C₄ alkyl group optionally interrupted orterminated by one or two moieties independently selected from O, NH, S,SO, SO₂ and C(O), or L represents a C₃-C₆ cycloalkyl, methylC₃-C₆cycloalkyl or C₃-C₆ cycloalkylmethyl group, each of the recited groupsbeing optionally substituted with one or two substituents independentlyselected from hydroxyl, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy and C₁-C₄ haloalkoxy.
 7. A compound according to claim 1, whereinL represents a C₃-C₄ alkylene chain, the ends of which are attached toadjacent ring carbon atoms in the 5- to 10-membered ring system of G² toform a ring.
 8. A compound according to claim 7, wherein the 5- to10-membered ring system of G² is phenyl.
 9. A compound according toclaim 1, wherein, in G²,the saturated or unsaturated 5- to 10-memberedring system is selected from cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptyl, cyclopentenyl, cyclohexenyl, phenyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,diazabicyclo[2.2.1]hept-2-yl, naphthyl, benzofuranyl, benzothienyl,benzodioxolyl, quinolinyl, 2,3-dihydrobenzofuranyl, tetrahydropyranyl,pyrazolyl, pyrazinyl, thiazolidinyl, indanyl, thienyl, isoxazolyl,pyridazinyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, indolyl,imidazolyl, pyrimidinyl, benzimidazolyl, triazolyl, tetrazolyl andpyridinyl.
 10. A compound according to claim 1, wherein, in G³,theunsaturated 5- to 10-membered ring system is selected fromcyclopentenyl, cyclohexenyl, phenyl, naphthyl, benzofuranyl,benzothienyl, benzodioxolyl, quinolinyl, 2,3-dihydrobenzofuranyl,pyrazolyl, pyrazinyl, thiazolidinyl, indanyl, thienyl, isoxazolyl,pyridazinyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, indolyl,imidazolyl, pyrimidinyl, benzimidazolyl, triazolyl, tetrazolyl andpyridinyl.
 11. A compound according to claim 1 which is selected fromthe group consisting of:2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-fluoro-biphenyl-4-yl)-ethyl]-acetamide,N-[2-(4′-Cyano-biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-(2-phenyl-cyclopropyl)-acetamide,N-[2-(4-Chlorophenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-(2-Biphenyl-4-yl-ethyl)-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(7-methyl-1H-indol-3-yl)ethyl]-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-phenoxyphenyl)ethyl]-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-fluorophenyl)ethyl]-acetamide,N-[2-(4-Bromophenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(2,4-Dichlorophenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(3′-Chloro-biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(4′-Benzyloxy-biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-thiophen-3-yl-phenyl)ethyl]-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-thiophen-2-yl-phenyl)ethyl]-acetamide,N-[2-(4′-Chloro-biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-methylsulfanyl-biphenyl-4-yl)ethyl]-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(3′-nitro-biphenyl-4-yl)ethyl]-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-methyl-biphenyl-4-yl)ethyl]-acetamide,N-[2-(3′-Acetylamino-biphenyl-4-yl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-naphthalen-2-yl-phenyl)ethyl]-acetamide,N-[2-(3′,5′-Dichloro-biphenyl-4-yl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(3′-methyl-biphenyl-4-yl)ethyl]-acetamide,N-[2-(4-Benzofuran-2-yl-phenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(3′-methoxy-biphenyl-4-yl)ethyl]-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-(2-[1,1′;4′,1″]terphenyl-4-ylethyl)-acetamide,N-[2-(4′-Acetyl-biphenyl-4-yl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(4-Benzo[b]thiophen-2-yl-phenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(4′-Cyanomethyl-biphenyl-4-yl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-pyridin-3-yl-phenyl)ethyl]-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[4-(1H-pyrrol-2-yl)phenyl]ethyl}-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-furan-3-yl-phenyl)ethyl]-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-furan-2-yl-phenyl)ethyl]-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-(2-thiophen-2-yl-ethyl)-acetamide,N-[2-(4-tert-Butylphenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(4-Chlorophenyl)-1-methylethyl]-2-(2,5-dioxoimidazolidin-4-yl)acetamide,N-{[1-(4-Chlorophenyl)cyclopropyl]methyl}-2-(2,5-dioxoimidazolidin-4-yl)acetamide,N-2,3-Dihydro-1H-inden-2-yl-2-(2,5-dioxoimidazolidin-4-yl)acetamide,N-[2-(4-Chlorophenyl)ethyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamide,N-[2-(4-Chlorophenyl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamide,N-[2-(4′-Cyano-1,1′-biphenyl-4-yl)ethyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamide,N-[2-(4′-Fluoro-1,1′-biphenyl-4-yl)ethyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-fluoro-1,1′-biphenyl-4-yl)propyl]-acetamide,N-[(1S,2R)-2-(4′-Methoxybiphenyl-4-yl)cyclopropyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[(1S,2R)-2-(4′-Cyanobiphenyl-4-yl)cyclopropyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[(1S,2R)-2-(4′-Acetylbiphenyl-4-yl)cyclopropyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-{(1S,2R)-2-[4′-(Acetylamino)biphenyl-4-yl]cyclopropyl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(4′-Cyanobiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(3′-methoxybiphenyl-4-yl)ethyl]-acetamide,N-[2-(4′-Cyano-3′-methylbiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-methyl-N-(2-phenylethyl)-acetamide,N-[1-(4-Chlorophenyl)ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-(2-hydroxy-1-methyl-2-phenylethyl)-acetamide,N-{2-[4-(1,3-Benzodioxol-5-yl)phenyl]propyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(3′-methoxybiphenyl-4-yl)propyl]-acetamide,N-{2-[3′-(Acetylamino)biphenyl-4-yl]propyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(3′-Acetylbiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(4′-Acetylbiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-{2-[4-(1-Benzothien-2-yl)phenyl]propyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(3′-Cyanobiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(4′-Cyanobiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-fluoro-3′-methylbiphenyl-4-yl)propyl]-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[3′-(methylthio)biphenyl-4-yl]propyl}-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[4-(6-methoxypyridin-3-yl)phenyl]propyl}-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4′-methoxy-3′-methylbiphenyl-4-yl)propyl]-acetamide,N-{2-[4-(2,3-Dihydro-1-benzofuran-5-yl)phenyl]propyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[3′-(trifluoromethoxy)biphenyl-4-yl]propyl}-acetamide,N-[2-(3′,4′-Dimethoxybiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-quinolin-3-ylphenyl)propyl]-acetamide,N-[2-(4′-Cyano-3′-methylbiphenyl-4-yl)propyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(1,3-Benzodioxol-5-yl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[5-(3-methoxyphenyl)-2,3-dihydro-1H-inden-2-yl]-acetamide,N-{5-[3-(Acetylamino)phenyl]-2,3-dihydro-1H-inden-2-yl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(3-Acetylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(4-Acetylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(1-Benzothien-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(3-Cyanophenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(4-Cyanophenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[5-(4-fluoro-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-{5-[3-(methylthio)phenyl]-2,3-dihydro-1H-inden-2-yl}-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[5-(6-methoxypyridin-3-yl)-2,3-dihydro-1H-inden-2-yl]-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[5-(4-methoxy-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-acetamide,5-(2,3-Dihydro-1-benzofuran-5-yl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)acetamide,N-[5-(3,4-Dimethoxyphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(4′-Fluorobiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-{2-[4-(1,3-Benzodioxol-5-yl)phenyl]propyl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(3′-Methoxybiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-{2-[4-(1-Benzothien-2-yl)phenyl]propyl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(3′-Cyanobiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(4′-Fluoro-3′methylbiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,2-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-{2-[3′-(methylthio)biphenyl-4-yl]propyl}-acetamide,N-{2-[4-(6-Methoxypyridin-3-yl)phenyl]propyl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(4′-Methoxy-3′-methylbiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-{2-[4-(2,3-Dihydro-1-benzofuran-5-yl)phenyl]propyl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,2-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-{2-[3′-(trifluoromethoxy)biphenyl-4-yl]propyl}-acetamide,N-[2-(3′,4′-Dimethoxybiphenyl-4-yl)propyl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,2-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-[2-(4-quinolin-3-ylphenyl)propyl]-acetamide,N-[5-(4-Fluorophenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(1,3-Benzodioxol-5-yl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(3-Methoxyphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-{5-[3-(Acetylamino)phenyl]-2,3-dihydro-1H-inden-2-yl}-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(3-Acetylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(4-Acetylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(1-Benzothien-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(3-Cyanophenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(4-Cyanophenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(4-Fluoro-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,2-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-{5-[3-(methylthio)phenyl]-2,3-dihydro-1H-inden-2-yl}-acetamide,N-[5-(6-Methoxypyridin-3-yl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(4-Methoxy-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(2,3-Dihydro-1-benzofuran-5-yl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,2-(4-Methyl-2,5-dioxoimidazolidin-4-yl)-N-{5-[3-(trifluoromethoxy)phenyl]-2,3-dihydro-1H-inden-2-yl}-acetamide,N-[5-(3,4-Dimethoxyphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,N-[5-(4-Cyano-3-methylphenyl)-2,3-dihydro-1H-inden-2-yl]-2-(4-methyl-2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-(2-{4-[4(trifluoromethyl)phenoxy]phenyl}ethyl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[4-(4-methoxyphenoxy)phenyl]ethyl}-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-(2-{4-[4-(trifluoromethoxy)phenoxy]phenyl}ethyl)-acetamide,N-{2-[4-(4-Chlorophenoxy)phenyl]ethyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-{2-[4-(4-Acetylphenoxy)phenyl]ethyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[4-(pyridin-3-yloxy)phenyl]ethyl}-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-(2-{4-[(6-methoxypyridin-3-yl)oxy]phenyl}ethyl)-acetamide,N-{2-[4-(4-Cyanophenoxy)phenyl]ethyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[4-(4-methylphenoxy)phenyl]ethyl}-acetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-{2-[4-(4-fluorophenoxy)phenyl]ethyl}-acetamide,N-(2-Biphenyl-4-yl-2-hydroxy-ethyl)-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(1,1′-Biphenyl-4-yl)-2-methoxyethyl]-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,N-[2-(1,1′-Biphenyl-4-yl)-ethyl]-2-(2,5-dioxoimidazolidin-4-yl)-N-methylacetamide,2-(2,5-Dioxoimidazolidin-4-yl)-N-[2-(4-phenylethynyl-piperidin-1-yl)ethyl]-acetamide,N-{2-[(4-Bromobenzyl)oxy]ethyl}-2-(2,5-dioxoimidazolidin-4-yl)-acetamide,2-(1,1′-Biphenyl-4-yl)-2-oxoethyl (2,5-dioxoimidazolidin-4-yl)acetate,and pharmaceutically acceptable salts and solvates thereof.
 12. Aprocess for the preparation of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof as defined in claim1 which comprises, (a) when X represents an oxygen atom or a group NR⁴,reacting a compound of formula

wherein X¹ represents an oxygen atom or a group NR⁴ and L, G² and R⁴ areas defined in claim 1, formula (I), with an activated carboxylic acid offormula

wherein Y, Z¹, Z², R¹, R² and R³ are as defined in claim 1, formula (I);or (b) when X represents CH₂, reacting an activated carboxylic acid offormula (IV) as defined in (a) above with methoxymethylamine or a saltthereof followed by reaction with a Grignard reagent of formula

wherein Hal represents a halogen atom and L and G² are as defined inclaim 1, formula (I); or (c) when X represents CH₂, reacting a compoundof formula

wherein Y, Z¹, Z², R¹, R² and R³ are as defined in claim 1 formula (I),with a compound of formula

wherein LG¹ represents a leaving group and L and G² are as defined inclaim 1 formula (I) in the presence of a strong base; and optionallyafter (a), (b) or (c) forming a pharmaceutically acceptable salt orsolvate.
 13. A pharmaceutical composition comprising a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof asclaimed in claim 1 and a pharmaceutically acceptable adjuvant, diluentor carrier.
 14. A process for the preparation of a pharmaceuticalcomposition which comprises mixing a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof as defined in claim1 with a pharmaceutically acceptable adjuvant, diluent or carrier.15-17. (canceled)
 18. A method of treating a disease or conditionmediated by MMP12 which comprises administering to a patient atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof as claimed inclaim
 1. 19. A method of treating an obstructive airways disease whichcomprises administering to a patient a therapeutically effective amountof a compound of formula (I) or a pharmaceutically acceptable salt orsolvate thereof as claimed in claim
 1. 20. The method of claim 19,wherein the obstructive airways disease is asthma or chronic obstructivepulmonary disease.